Etp derivatives

ABSTRACT

Provided herein, inter alia, is the synthesis of ETP derivatives. The uses of the ETP derivatives described herein include treatment of cancer.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/689,682, filed Apr. 17, 2015, which is a continuation ofInternational Application No. PCT/US2013/066252, filed Oct. 22, 2013,which claims priority to U.S. Provisional Application No. 61/716,803,filed Oct. 22, 2012, and to U.S. Provisional Application No. 61/799,160,filed Mar. 15, 2013. The disclosure of each of the prior applications isconsidered part of and is incorporated by reference in the disclosure ofthis application.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

This invention was made with government support under grant2R01-GM030859 and 5F32GM090473 awarded by the NIH National Institute ofGeneral Medical Sciences. The government has certain rights in theinvention.

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED AS AN ASCII FILE

The Sequence Listing written in file 48440-514C01US_ST25.TXT, created onAug. 18, 2016, 1,673 bytes, machine format IBM-PC, MS-Windows operatingsystem, is hereby incorporated by reference.

BACKGROUND OF THE INVENTION

ETP natural products represent an intriguing class of (typically) fungalsecondary metabolites with a large variety of biological activitiesranging from antibiotic to antiviral to antimalarial properties. Highlevels of toxicity, however, has so far prevented any clinical studiesof known ETP structures. No detailed SAR studies of ETPs and theiranalogues have been reported to date. Furthermore, introduction andelaboration of functional groups for ETP structures has not beenpreviously reported thereby preventing modification of crucialproperties such as water solubility, membrane permeability or metabolicstability in biological systems. Accordingly a synthetic route tosynthesize ETP analogues for medicinal purposes is crucial and hassignificant value. Provided herein are solutions to these and otherproblems in the art.

BRIEF SUMMARY OF THE INVENTION

Provided herein, inter alia, are synthetic analogues of ETP compounds.The analogues may be used in the treatment of cancer and may beeffective as synergistically combined with other cancer treatingcompounds. Methods of synthesizing and use are also provided.

In a first aspect is a compound having the formula:

The symbol p is 2, 3 or 4. R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33A), —NR^(34A)R^(35A), —COOR^(33A),—CONR^(34A)R^(35A), —NO₂, —SR^(36A), —SO_(n1)R^(34A), —SO_(n1)OR^(34A),—SO_(n1)NR^(34A)R^(35A), —NHNR^(34A)R^(35A), —ONR^(34A)R^(35A),—NHC(O)NHNR^(34A)R^(35A), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. R² ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33B),—NR^(34B)R^(35B), —COOR^(33B), —CONR^(34B)R^(35B), —NO₂, —SR^(36B),—SO_(n2)R^(34b), —SO_(n2)OR^(34B), —SO_(n2)NR^(34B)R^(35B),—NHR^(34B)R^(35B), —ONR^(34B)R^(35B), —NHC(O)NHNR^(34B)R^(35B),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R³ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33C), —NR^(34C)R^(35C),—COOR^(33C), —CONR^(34C)R^(35C), —NO₂, —SR^(36C), —SO_(n3)R^(34C),—SO_(n3)OR^(34C), —SO_(n3)NR^(34C)R^(35C), —NHNR³⁴R^(35C),—ONR^(34C)R^(35C), —ONR³⁴R^(35C), —NHC(O)NHNR^(34C)R^(35C), substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33D), —NR^(34D)R^(35D), —COOR^(33D),—CONR^(34D)R^(35D), —NO₂, —SR^(36D), —SO_(n4)R^(34D), —SO_(n4)OR^(34D),—SO_(n4)NR^(34D)R^(35D), —NHNR^(34D)R^(35D), —ONR^(34D)R^(35D),—NHC(O)NHNR^(34D)R^(35D), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. R⁵ ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33E),—NR^(34E)R^(35E), —COOR^(33E), —CONR^(34E)R^(35E), —NO₂, —SR^(36E),—SO_(n5)R^(34E), —SO_(n5)OR^(34E), —SO_(n5)NR^(34E)R^(35E),—NHNR^(34E)R^(35E), —ONR^(34E)R^(35E), —NHC(O)NHNR^(34E)R^(35E),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R⁶ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33F), —NR^(34F)R^(35F),—COOR^(33F), —CONR^(34F)R^(35F), —NO₂, —SR^(36F), —SO_(n6)R^(34F),—SO_(n6)OR^(34F), —SO_(n6)NR^(34F)R^(35F), —NHNR^(34F)R^(35F),—ONR^(34F)R^(35F), —NHC(O)NHNR^(34F)R^(35F), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R¹⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33G), —NR^(34G)R^(35G), —COOR^(33G),—CONR^(34G)R^(35G), —NO₂, —SR^(36G), —SO_(n7)R^(34G), —SO_(n7)OR^(34G),—SO_(n7)NR^(34G)R^(35G), —NHNR^(34G)R^(35G), —ONR^(34G)R^(35G),—NHC(O)NHNR^(34G)R^(35G), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. R¹⁸is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(33H), —NR^(34H)R^(35H), —COOR^(33H), —CONR^(34H)R^(35H), —NO₂,—SR^(36H), —SO_(n8)R^(34H), —SO_(n8)OR^(34H), —SO_(n8)NR^(34H)R^(35H),—NHNR^(34H)R^(35H), —ONR^(34H)R^(35H), —NHC(O)NHNR^(34H)R^(35H),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R^(33A), R^(34A), R^(35A),R^(36A), R^(33B), R^(34B), R^(35B), R^(36B), R^(33C), R^(34C), R^(35C),R^(36C), R^(33D), R^(34D), R^(35D), R^(36D), R^(33E), R^(34E), R^(35E),R^(36E), R^(33F), R^(34F), R^(35F), R^(36F), R^(33G), R^(34G), R^(35G),R^(36G), R^(33H), R^(34H), R^(35H), and R^(36H) are independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. Thesymbol n1, n2, n3, n4, n5, n6, n7, and n8 are independently 1 or 2.

In another aspect is a compound having the formula:

R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(33A), —NR^(34A)R^(35A), —COOR^(33A), —CONR^(34A)R^(35A), —NO₂,—SR^(36A), —SO_(n1)R^(34A), —SO_(n1)OR^(34A), —SO_(n1)NR^(34A)R^(35A),—NHNR^(34A)R^(35A), —ONR^(34A)R^(35A), —NHC(O)NHNR^(34A)R^(35A),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R² is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33B), —NR^(34B)R^(35B),—COOR^(33B), —CONR^(34B)R^(35B), —NO₂, —SR^(36B), —SO_(n2)R^(34b),—SO_(n2)OR^(34B), —SO_(n2)NR^(34B)R^(35B), —NHNR^(34B)R^(35B),—ONR^(34B)R^(35B), —NHC(O)NHNR^(34B)R^(35B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33C), —NR^(34C)R^(35C), —COOR^(33C),—CONR^(34C)R^(35C), —NO₂, —SR^(36C), —SO_(n3)R^(34C), —SO_(n3)OR^(34C),—SO_(n3)NR^(34C)R^(35C), —NHNR^(34C)R^(35C), —ONR^(34C)R^(35C),—NHC(O)NHNR^(34C)R^(35C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. R⁴ ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33D),—NR^(34D)R^(35D), —COOR^(33D), —CONR^(34D)R^(35D), —NO₂, —SR^(36D),—SO_(n4)R^(34D), —SO_(n4)OR^(34D), —SO_(n4)NR^(34D)R^(35D),—NR^(34D)R^(35D), —ONR^(34D)R^(35D), —NHC(O)NHNR^(34D)R^(35D),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R⁵ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33E), —NR^(34E)R^(35E),—COOR^(33E), —CONR^(34E)R^(35E), —NO₂, —SR^(36E), —SO_(n5)R^(34E),—SO_(n5)OR^(34E), —SO_(n5)NR^(34E)R^(35E), —NHNR^(34E)R^(35E),—ONR^(34E)R^(35E), —NHC(O)NHNR^(34E)R^(35E), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33F), —NR^(34F)R^(35F), —COOR^(33F),—CONR^(34F)R^(35F), —NO₂, —SR^(36F), —SO_(n6)R^(34F), —SO_(n6)OR^(34F),—SO_(n6)NR^(34F)R^(35F), —NHNR^(34F)R^(35F), —ONR^(34F)R^(35F),—NHC(O)NHNR^(34F)R^(35F), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. R¹⁶is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(33G), —NR^(34G)R^(35G), —COOR^(33G), —CONR^(34G)R^(35G), —NO₂,—SR^(36G), —SO_(n7)R^(34G), —SO_(n7)OR^(34G), —SO_(n7)NR^(34G)R^(35G),—NHNR^(34G)R^(35G), —ONR^(34G)R^(35G), —NHC(O)NHNR^(34G)R^(35G),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R¹⁸ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33H), —NR^(34H)R^(35H),—COOR^(33H), —CONR^(34H)R^(35H), —NO₂, —SR^(36H), —SO_(n8)R^(34H),—SO_(n8)OR^(34H), —SO_(n8)NR^(34H)R^(35H), —NHNR^(34H)R^(35H),—ONR^(34H)R^(35H), —NHC(O)NHNR^(34H)R^(35H), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R^(33A), R^(34A), R^(35A), R^(36A), R^(33B),R^(34B), R^(35B), R^(36B), R^(33C), R^(34C), R^(35C), R^(36C), R^(33D),R^(34D), R^(35D), R^(36D), R^(33E), R^(34E), R^(35E), R^(36E), R^(33F),R^(34F), R^(35F), R^(36F), R^(33G), R^(34G), R^(35G), R^(36G), R^(33H),R^(34H), R^(35H), and R^(36H) are independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. The symbol n1, n2, n3, n4, n5, n6, n7, and n8are independently 1 or 2. R²⁵ and R²⁶ are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

In another aspect is a compound having formula:

R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(33A), —NR^(34A)R^(35A), —COOR^(33A), —CONR^(34A)R^(35A), —NO₂,—SR^(36A), —SO_(n1)R^(34A), —SO_(n1)OR^(34A), —SO_(n1)NR^(34A)R^(35A),—NHNR^(34A)R^(35A), —ONR^(34A)R^(35A), —NHC(O)NHNR^(34A)R^(35A),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R² is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33B), —NR^(34B)R^(35B),—COOR^(33B), —CONR^(34B)R^(35B), —NO₂, —SR^(36B), —SO_(n2)R^(34b),—SO_(n2)OR^(34B), —SO_(n2)NR^(34B)R^(35B), —NHNR^(34B)R^(35B),—ONR^(34B)R^(35B), —NHC(O)NHNR^(34B)R^(35B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R³ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33C), —NR^(34C)R^(35C), —COOR^(33C),—CONR^(34C)R^(35C), —NO₂, —SR^(36C), —SO_(n3)R^(34C), —SO_(n3)OR^(34C),—SO_(n3)NR^(34C)R^(35C), —NHNR^(34C)R^(35C), —ONR^(34C)R^(35C),—NHC(O)NHNR^(34C)R^(35C), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. R⁴ ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33D),—NR^(34D)R^(35D), —COOR^(33D), —CONR^(34D)R^(35D), —NO₂, —SR^(36D),—SO_(n4)R^(34D), —SO_(n4)OR^(34D), —SO_(n4)NR^(34D)R^(35D),—NHNR^(34D)R^(35D), —ONR^(34D)R^(35D), —NHC(O)NHNR^(34D)R^(35D),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R⁵ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33E), —NR^(34E)R^(35E),—COOR^(33E), —CONR^(34E)R^(35E), —NO₂, —SR^(36E), —SO_(n5)R^(34E),—SO_(n5)OR^(34E), —SO_(n5)NR^(34E)R^(35E), —NHNR^(34E)R^(35E),—ONR^(34E)R^(35E), —NHC(O)NHNR^(34E)R^(35E), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33F), —NR^(34F)R^(35F), —COOR^(33F),—CONR^(34F)R^(35F), —NO₂, —SR^(36F), —SO_(n6)R^(34F), —SO_(n6)OR^(34F),—SO_(n6)NR^(34F)R^(35F), —NHNR^(34F)R^(35F), —ONR^(34F)R^(35F),—NHC(O)NHNR^(34F)R^(35F), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. R¹⁶is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(33G), —NR^(34G)R^(35G), —COOR^(33G), —CONR^(34G)R^(35G), —NO₂,—SR^(36G), —SO_(n7)R^(34G), —SO_(n7)OR^(34G), —SO_(n7)NR^(34G)R^(35G),—NHNR^(34G)R^(35G), —ONR^(34G)R^(35G), —NHC(O)NHNR^(34G)R^(35G),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R¹⁸ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33H), —NR^(34H)R^(35H),—COOR^(33H), —CONR^(34H)R^(35H), —NO₂, —SR^(36H), —SO_(n8)R^(34H),—SO_(n8)OR^(34H), —SO_(n8)NR^(34H)R^(35H), —NHNR^(34H)R^(35H),—ONR^(34H)R^(35H), —NHC(O)NHNR^(34H)R^(35H), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R^(33A), R^(34A), R^(35A), R^(36A), R^(33B),R^(34B), R^(35B), R^(36B), R^(33C), R^(34C), R^(35C), R^(36C), R^(33D),R^(34D), R^(35D), R^(36D), R^(33E), R^(34E), R^(35E), R^(36E), R^(33F),R^(34F), R^(35F), R^(36F), R^(33G), R^(34G), R^(35G), R^(36G), R^(33H),R^(34H), R^(35H), and R^(36H) are independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. The symbol n1, n2, n3, n4, n5, n6, n7, and n8are independently 1 or 2.

In another aspect a pharmaceutical composition is provided. Thepharmaceutical composition includes a compound as provided herein (e.g.of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), or (XVIII)) and apharmaceutically acceptable excipient.

In another aspect, a pharmaceutical composition is provided including acompound as provided herein (e.g. of formula (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV),(XVI), (XVII), or (XVIII)), a pharmaceutically acceptable excipient, andat least one additional anticancer agent.

In another aspect a method of treating cancer is provided. The methodincludes administering to a subject in need thereof a therapeuticallyeffective amount of a compound of formula (I), (II), (III), (IV), (V),(VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI),(XVII), or (XVIII)), including embodiments thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Synthesis of racemic ETP derivatives herein: the three stepsynthesis results in a 5:1 ratio of epimeric derivatives 3 and 4.

FIG. 2: Synthesis of ETP69: installation of the disulfide bridge resultsin compounds 5 (e.g. ETP69) and compound 6 with an overall 10% yield.

FIG. 3: Enantioselective synthetic route for ETP derivatives:enantiomerically pure (S) and (R) derivatives of ETP derivatives may besynthesized from racemic starting material 1.

FIG. 4: Comparison of ETP69 enantiomeric activity on MOLM-13 AML cells.The (S) enantiomer of ETP69 shows about a 4× fold increase in inhibitorycapacity when compared to the (R) enantiomer.

FIG. 5: Testing of enantiomerically pure ETP69 shows the (S) enantiomerto be slightly more active than the racemic mixture or the (R)enantiomer; compounds where tested in 10-dose IC₅₀ mode with 3-foldserial dilution starting at 10 μM; curve fits were performed with theactivities at the highest concentration of compounds were less than 65%.

FIGS. 6A-6C: Testing of ETP analogues described herein against variouscancer cell lines: FIG. 6A) shows viability inhibition on DU145 prostatecancer cells, A2058 melanoma cells, and SKOV3 ovarian cancer cells byETP analogues described herein; FIG. 6B) shows viability inhibition onHCC38, HCC1937, MDA-MB-231, and MDA-MB-468 triple negative breast cancercells after administration of ETP69; FIG. 6C) shows inhibition of H3K9trimethylation by ETP69 in A2058 melanoma cells.

FIG. 7: ETP69 selectively inhibits SUV39H1 and G9a in vitro. Comparisonof inhibition of ETP69 and known HMT inhibitor Chaetocin shows SUV39H1and G9a selectivity inhibited by ETP69.

FIG. 8: ETP derivatives induce p16 tumor suppressor. ETP69 induces p16tumor suppressor in DU145 prostate cancer cells and A2058 melanomacells. *SKOV3 ovarian cancer cells and A549 non-small cell lung cancercells are p16-null.

FIG. 9: ETP derivatives induce p53 tumor suppressor, p21WAF1cyclin-dependent kinase inhibitor 1 and Cyclin-dependent kinaseinhibitor 1B p27(Kip1): ETP69 induces p53, p21WAF1 and p27(Kip1) inA2058 melanoma cells, DU145 prostate cancer cells, A549 lung cancercells, and SKOV3 ovarian cancer cells. *SKOV3 cells do not express p53protein.

FIG. 10: FLT3 assays with ETP derivative ETP69: Fms-like tyrosine kinase3 (FLT3) expressed in AMLs is not directly inhibited by ETP69 (S)enantiomer showing antitumor activities from ETP derivatives is not aresult of FLT3 inhibition. MV4-11 and MOLM-13 AML cells have internaltandem duplications of FLT3 (FLT-ITD)—these mutations result in a lowoutcome with a higher relapse rate.

FIG. 11: Effect of ETP69 on SKOV3 ovarian cancer cells: ETP69 inducesapoptosis of SKOV3 ovarian cancer cells.

FIGS. 12A-12D: Synergystic effect of ETP and epigenetic inhibitors.ETP69 and azacitidine exhibit a greater effect on reducing viabilitiesof SKOV3 ovarian cells than when administered alone. FIG. 12A: 1 μMazacitidine; FIG. 12B: 2.5 μM azacitidine; FIG. 12C: 5 μM azacitidine;FIG. 12D: 10 μM azacitidine.

FIGS. 13-13C: Synergystic effect of ETP and epigenetic inhibitors. ETP69and decitabine exhibit a greater effect on reducing viabilities of SKOV3ovarian cells than when administered alone. FIG. 13A: 0.1 μM decitabine;FIG. 13B: 0.25 μM decitabine; FIG. 13C: 1 μM decitabine.

FIGS. 14-14C: Synergystic effect of ETP derivatives and multi-kinaseinhibitors. ETP 69 and sorafenib exhibit a greater effect on reducingviabilities of A549 non-small cell lung cancer cells than whenadminister alone. FIG. 14A: 2.5 μM Sorafenib; FIG. 14B: 5 μM Sorafenib;FIG. 14C: 10 μM Sorafenib.

FIGS. 15A-15B: Efficacy of ETP69 on A549 lung cancer SQ xenografts. FIG.15A: Treatment with ETP69 results in decreased tumor volume and tumorweight of mice with no observable toxicity symptoms. FIG. 15B: Histogramof tumor weight for vehicle (left column) and ETP59 (right column).

FIGS. 16A-16B: Efficacy of ETP69 on A2058 melanoma SQ xenografts. FIG.16A: Treatment with ETP69 results in decreased tumor volume and tumorweight of mice with no observable toxicity symptoms. FIG. 16B: Histogramof tumor weight for vehicle (left column) and ETP59 (right column).

FIGS. 17A-17B: Efficacy of ETP69 on SKOV3 xenografts. Treatment withETP69 results in decreased tumor volume and tumor weight of mice (FIG.17A) with no observable toxicity symptoms (FIG. 17B).

FIGS. 18A-18B: Efficacy of ETP417 on MV4-11 AML SQ xenografts: Treatmentwith ETP417 results in decreased tumor volume and tumor weight of mice(FIG. 18A) with no observable toxicity symptoms (FIG. 18B).

FIG. 19: Pharmacokinetic parameters for intraperitoneal administrationof ETP69 in male CD-1 mice: C₀: Maximum plasma concentrationextrapolated to t=0; t_(max): Time of maximum plasma concentration;t_(1/2): half-life, data points used for half-life determination are inbold; AUC_(last): Area Under the Curve, calculated to the lastobservable time point; AUC_(∞): Area Under the Curve, extrapolated toinfinity; ND: Not Determined; BLOQ: Below the limit of quantitation (2.5ng/mL); ^(a)Values are estimates because the correlation coefficient forthe half-life determination was <0.85 (actual value was 0.838).

FIG. 20: Pharmacokinetic parameters for oral administration of ETP69 inmale CD-1 mice: C₀: Maximum plasma concentration extrapolated to t=0;t_(max): Time of maximum plasma concentration; t_(1/2): half-life, datapoints used for half-life determination are in bold; AUC_(last): AreaUnder the Curve, calculated to the last observable time point; AUC_(∞):Area Under the Curve, extrapolated to infinity; ND: Not Determined;BLOQ: Below the limit of quantitation (2.5 ng/mL)

FIG. 21: Effect of ETP69 on A549 lung cancer cells: ETP69 displaysantitumor activities with IC50 of 0.1 uM against A549 non-small celllung cancer cells.

FIGS. 22A-22B: Effect of ETP69 on liver cancer cells: ETP69 displaysIC₅₀ values of 3.3 nM and 13.8 nM against Huh-7 (FIG. 22A) and HepG2(FIG. 22B) heapatocullular carcinoma cells respectively.

FIG. 23: Effect of ETP69 on pancreatic cancer cells: ETP69 displays IC₅₀values of 86 nM, 210 nM and 824 nM against Su.86.86, BxPC3, and Panc1pancreatic cancer cell lines respectively.

FIGS. 24A-24C: Effect of ETP69 on MV4-11 AML (FIG. 24A), KCL-22 CML(FIG. 24B) and T315I mutant KCL-22 CML cells (FIG. 24C): ETP69 displaysIC₅₀ values of 1.8 nM, 180 nM, and 170 nM against MV4-11 AML, KCL-22 CMLand T315I mutant KCL-22 CML cells respectively.

FIGS. 25-25B: Effect of ETP enantiomers on activity against AML cells:ETP417 (e.g. S enantiomer) has significantly greater activity than itscorresponding R enantiomer (ETP422). FIG. 25A: MOLM13 AML cells; FIG.25B: MV4-12 AML cells.

FIG. 26: SUV39H1 expression levels in normal pancreas and Panc1 cancercells: normal pancrease cells express less SUV39H1 than the Panc1 cancercell line.

FIG. 27: Stable SUV39H1 Knockdown in Pancreatic Cancer Cells: SUV39H1expression levels of BxPC3, SU.86.86 and Panc1 cells expressing SUV39H1shRNA are reduced by 73%, 77% and 90%, respectively, compared tounmodified cells. Cell lines expressing a non-targeting control shRNA(NT) were generated as controls.

FIG. 28: p53 Up-Regulation Following SUV39H1 Knockdown or Treatment withETP69 in Panc1 cells: Treatment with increasing concentrations (100nM-500 nM) of ETP69 or shRNA-mediated knockdown of SUV39H1 leadsto >3-fold up-regulation of p53 in Panc1 cells.

FIG. 29: SUV39H1 knockdown increases senescence in pancreatic cancercells Senescence-associated b-galactosidase activity: SU.86.86 andPanc-1 cells expressing SUV39H1shRNA show increasedsenescence-associated beta-galactosidase activity, as evidenced by thestain. No senescence-associated beta-galactosidase activity was detectedin the control cells expressing a non-targeting (NT) shRNA.

FIG. 30: SUV39H1 Knockdown Increases Senescence in SU.86.86: SU.86.86cells expressing SUV39H1shRNA show increased senescence-associatedbeta-galactosidase activity, as evidenced by the blue stain. Nosenescence-associated beta-galactosidase activity was detected in thecontrol cells expressing a non-targeting (NT) shRNA.

FIG. 31: ETP69 induces senescence in Panc1 cancer cells insenescence-associate beta-galactosidase activity: Panc1 pancreaticcancer cells treated with ETP69 for 5 days show increasedsenescence-associated beta-galactosidase activity (blue stain) comparedto Panc1 cells treated with DMSO (vehicle control).

FIG. 32: SUV31H1 knockdown assay decreases cell mobility in woundhealing assay. BxPC3 cells expressing (shRNA-mediated) low levels ofSUV39H1 migrate into denuded areas (between the arrows) in cellmonolayers at a lower rate than unmodified BxPC3 cells, failing to closethe “wound” within 24 h.

FIG. 33: Viability of normal pancreatic epithelial cells after treatmentwith ETP69: treatment of normal pancreatic epithelial cells with ETP69at doses from 100 nM to 1000 nM shows little destruction of normalpancreatic cells but significant killing of cells from BxPC3 and SU86.86pancreatic cancer cell lines.

FIG. 34: Effect of racemic and enantiomers on colon cancer cells: ETP417displays greater viability inhibition on HCT116 colon cancer cells thanETP422 and the ETP69.

FIG. 35 Inhibition of various HMTs, histone acetyltransferases (HAT) andDNMTs: ETP69 shows specific inhibition of HMT SUV31H1 and G9a, but notHAT p300 and DNMT1.

FIG. 36: CD Data for the two enantiomers of ETP69: (3S,6S,7S,8aS):t_(ret)=1.40 min (red); (3R,6R,7R,8aR): t_(ret)=2.11 min (blue) in EtOH(c≈10⁻⁴ M). See text for details.

DETAILED DESCRIPTION I. Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchedcarbon chain (or carbon), or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include mono-, di- andmultivalent radicals, having the number of carbon atoms designated(i.e., C₁-C₁₀ means one to ten carbons). Examples of saturatedhydrocarbon radicals include, but are not limited to, groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example,n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkylgroup is one having one or more double bonds or triple bonds. Examplesof unsaturated alkyl groups include, but are not limited to, vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers. An alkoxy is an alkyl attached to theremainder of the molecule via an oxygen linker (—O—).

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred in the presentinvention. A “lower alkyl” or “lower alkylene” is a shorter chain alkylor alkylene group, generally having eight or fewer carbon atoms. Theterm “alkenylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkene.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcombinations thereof, including at least one carbon atom and at leastone heteroatom selected from the group consisting of O, N, P, Si, and S,and wherein the nitrogen and sulfur atoms may optionally be oxidized,and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) O, N, P, S, B, As, and Si may be placed at any interiorposition of the heteroalkyl group or at the position at which the alkylgroup is attached to the remainder of the molecule. Examples include,but are not limited to: —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃,—CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and —CN. Up to two or threeheteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃.

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl,and the like. Examples of heterocycloalkyl include, but are not limitedto, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means adivalent radical derived from a cycloalkyl and heterocycloalkyl,respectively.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. The term “heteroaryl” refers to aryl groups (or rings)that contain at least one heteroatom such as N, O, or S, wherein thenitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. Thus, the term “heteroaryl” includesfused ring heteroaryl groups (i.e., multiple rings fused togetherwherein at least one of the fused rings is a heteroaromatic ring). A5,6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 5 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. Likewise, a 6,6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 6members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to tworings fused together, wherein one ring has 6 members and the other ringhas 5 members, and wherein at least one ring is a heteroaryl ring. Aheteroaryl group can be attached to the remainder of the moleculethrough a carbon or heteroatom. Non-limiting examples of aryl andheteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl,4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl. Substituents for each of the above noted aryl and heteroarylring systems are selected from the group of acceptable substituentsdescribed below. An “arylene” and a “heteroarylene,” alone or as part ofanother substituent, mean a divalent radical derived from an aryl andheteroaryl, respectively. A heteroaryl group substituent may be a —O—bonded to a ring heteroatom nitrogen.

A “fused ring aryl-heterocycloalkyl” is an aryl fused to aheterocycloalkyl. A “fused ring heteroaryl-heterocycloalkyl” is aheteroaryl fused to a heterocycloalkyl. A “fused ringheterocycloalkyl-cycloalkyl” is a heterocycloalkyl fused to acycloalkyl. A “fused ring heterocycloalkyl-heterocycloalkyl” is aheterocycloalkyl fused to another heterocycloalkyl. Fused ringaryl-heterocycloalkyl, fused ring heteroaryl-heterocycloalkyl, fusedring heterocycloalkyl-cycloalkyl, or fused ringheterocycloalkyl-heterocycloalkyl may each independently beunsubstituted or substituted with one or more of the substitutentsdescribed herein. Fused ring aryl-heterocycloalkyl, fused ringheteroaryl-heterocycloalkyl, fused ring heterocycloalkyl-cycloalkyl, orfused ring heterocycloalkyl-heterocycloalkyl may each independently benamed according to the size of each of the fused rings. Thus, forexample, 6,5 aryl-heterocycloalkyl fused ring describes a 6 memberedaryl moiety fused to a 5 membered heterocycloalkyl. Spirocyclic ringsare two or more rings wherein adjacent rings are attached through asingle atom. The individual rings within spirocyclic rings may beidentical or different. Individual rings in spirocyclic rings may besubstituted or unsubstituted and may have different substituents fromother individual rings within a set of spirocyclic rings. Possiblesubstituents for individual rings within spirocyclic rings are thepossible substituents for the same ring when not part of spirocyclicrings (e.g. substitutents for cycloalkyl or heterocycloalkyl rings).Spirocylic rings may be substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heterocycloalkylene andindividual rings within a spirocyclic ring group may be any of theimmediately previous list, including having all rings of one type (e.g.all rings being substituted heterocycloalkylene wherein each ring may bethe same or different substituted heterocycloalkylene). When referringto a spirocyclic ring system, heterocyclic spirocyclic rings means aspirocyclic rings wherein at least one ring is a heterocyclic ring andwherein each ring may be a different ring. When referring to aspirocyclic ring system, substituted spirocyclic rings means that atleast one ring is substituted and each substituent may optionally bedifferent.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “thio,” as used herein, means a sulfur that is single bonded tocarbon or to another sulfur.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and“heteroaryl”) includes both substituted and unsubstituted forms of theindicated radical. Preferred substituents for each type of radical areprovided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″,—ONR′R″, —NR′C═(O)NR″NR′″R″″, —CN, —NO₂, —NR′SO₂R″, —NR′C═(O)R″,—NR′C(O)—OR″, —NR′OR″, in a number ranging from zero to (2-m′+1), wherem′ is the total number of carbon atoms in such radical. R, R′, R″, R′″,and R″″ each preferably independently refer to hydrogen, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl (e.g., aryl substituted with 1-3 halogens),substituted or unsubstituted heteroaryl, substituted or unsubstitutedalkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When acompound of the invention includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R′″,and R″″ group when more than one of these groups is present. When R′ andR″ are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example,—NR′R″ includes, but is not limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″, —ONR′R″,—NR′C═(O)NR″NR′″R″″, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, —NR′SO₂R″, —NR′C═(O)R″, —NR′C(O)—OR″, —NR′OR″,in a number ranging from zero to the total number of open valences onthe aromatic ring system; and where R′, R″, R′″, and R″″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl. When a compound of the invention includes more than one Rgroup, for example, each of the R groups is independently selected asare each R′, R″, R′″, and R″″ groups when more than one of these groupsis present.

Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl,heteroaryl, cycloalkylene, heterocycloalkylene, arylene, orheteroarylene) may be depicted as substituents on the ring rather thanon a specific atom of a ring (commonly referred to as a floatingsubstituent). In such a case, the substituent may be attached to any ofthe ring atoms (obeying the rules of chemical valency) and in the caseof fused rings or spirocyclic rings, a substituent depicted asassociated with one member of the fused rings or spirocyclic rings (afloating substituent on a single ring), may be a substituent on any ofthe fused rings or spirocyclic rings (a floating substituent on multiplerings). When a substituent is attached to a ring, but not a specificatom (a floating substituent), and a subscript for the substituent is aninteger greater than one, the multiple substituents may be on the sameatom, same ring, different atoms, different fused rings, differentspirocyclic rings, and each substituent may optionally be different.Where a point of attachment of a ring to the remainder of a molecule isnot limited to a single atom (a floating substituent), the attachmentpoint may be any atom of the ring and in the case of a fused ring orspirocyclic ring, any atom of any of the fused rings or spirocyclicrings while obeying the rules of chemical valency. Where a ring, fusedrings, or spirocyclic rings contain one or more ring heteroatoms and thering, fused rings, or spirocyclic rings are shown with one more morefloating substituents (including, but not limited to, points ofattachment to the remainder of the molecule), the floating substituentsmay be bonded to the heteroatoms. Where the ring heteroatoms are shownbound to one or more hydrogens (e.g. a ring nitrogen with two bonds toring atoms and a third bond to a hydrogen) in the structure or formulawith the floating substituent, when the heteroatom is bonded to thefloating substituent, the substituent will be understood to replace thehydrogen, while obeying the rules of chemical valency.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)-U-, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)-B-, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′—(C″R″R′″)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″, and R′″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), Boron(B), Arsenic (As), and silicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

-   -   (A) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,        —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,        —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,        —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl, unsubstituted        heteroalkyl, unsubstituted cycloalkyl, unsubstituted        heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl,        and    -   (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, substituted with at least one substituent selected        from:        -   (i) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,            —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,            —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,            —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl, unsubstituted            heteroalkyl, unsubstituted cycloalkyl, unsubstituted            heterocycloalkyl, unsubstituted aryl, unsubstituted            heteroaryl, and        -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            and heteroaryl, substituted with at least one substituent            selected from:            -   (a) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,                —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,                —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,                —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl,                unsubstituted heteroalkyl, unsubstituted cycloalkyl,                unsubstituted heterocycloalkyl, unsubstituted aryl,                unsubstituted heteroaryl, and            -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,                aryl, or heteroaryl, substituted with at least one                substituent selected from: oxo, halogen, —CF₃, —CN, —OH,                —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H,                —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,                —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,                unsubstituted alkyl, unsubstituted heteroalkyl,                unsubstituted cycloalkyl, unsubstituted                heterocycloalkyl, unsubstituted aryl, and unsubstituted                heteroaryl.

A “size-limited substituent” or “size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, and each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl.

In some embodiments, each substituted group described in the compoundsherein is substituted with at least one substituent group. Morespecifically, in some embodiments, each substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In other embodiments, at least one or allof these groups are substituted with at least one size-limitedsubstituent group. In other embodiments, at least one or all of thesegroups are substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, and/or each substituted or unsubstituted heterocycloalkyl isa substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, and/or each substituted or unsubstitutedheterocycloalkylene is a substituted or unsubstituted 3 to 8 memberedheterocycloalkylene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, and/or each substitutedor unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to7 membered heterocycloalkyl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, and/or each substituted or unsubstitutedheterocycloalkylene is a substituted or unsubstituted 3 to 7 memberedheterocycloalkylene.

Certain compounds of the present invention possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisometricforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers areencompassed within the scope of the present invention. The compounds ofthe present invention do not include those which are known in art to betoo unstable to synthesize and/or isolate. The present invention ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds, generally recognized as stable bythose skilled in the art, are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

“S_(p)”, “S_(t)”, or “S_(n)” refers to a sulfide bridge having p, t, orn sulfurs (e.g. S₂ is —S—S—, S₃ is —S—S—S—, S₄ is —S—S—S—S—).

The terms “a” or “an,” as used in herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls.

Moreover, where a moiety is substituted with an R substituent, the groupmay be referred to as “R-substituted.” Where a moiety is R-substituted,the moiety is substituted with at least one R substituent and each Rsubstituent is optionally different. Where a particular R group ispresent in the description of a chemical genus (such as Formula (I)), aRoman alphabetic symbol may be used to distinguish each appearance ofthat particular R group. For example, where multiple R¹³ substituentsare present, each R¹³ substituent may be distinguished as R^(13A),R^(13B), R^(13C), R^(13D) etc., wherein each of R^(13A), R^(13B),R^(13C), R^(13D), etc. is defined within the scope of the definition ofR¹³ and optionally differently.

Description of compounds of the present invention is limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, and several known physiological conditions. Forexample, a heterocycloalkyl or heteroaryl is attached to the remainderof the molecule via a ring heteroatom in compliance with principles ofchemical bonding known to those skilled in the art thereby avoidinginherently unstable compounds.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and thelike. Also included are salts of amino acids such as arginate and thelike, and salts of organic acids like glucuronic or galactunoric acidsand the like (see, for example, Berge et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

Thus, the compounds of the present invention may exist as salts, such aswith pharmaceutically acceptable acids. The present invention includessuch salts. Examples of such salts include hydrochlorides,hydrobromides, sulfates, methanesulfonates, nitrates, maleates,acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates,(−)-tartrates, or mixtures thereof including racemic mixtures),succinates, benzoates, and salts with amino acids such as glutamic acid.These salts may be prepared by methods known to those skilled in theart.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereininclude those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

As used herein, the term “salt” refers to acid or base salts of thecompounds used in the methods of the present invention. Illustrativeexamples of acceptable salts are mineral acid (hydrochloric acid,hydrobromic acid, phosphoric acid, and the like) salts, organic acid(acetic acid, propionic acid, glutamic acid, citric acid and the like)salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like)salts.

The terms “treating”, or “treatment” refers to any indicia of success inthe treatment or amelioration of an injury, disease, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; improving a patient's physical or mental well-being.The treatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. The term“treating” and conjugations thereof, include prevention of an injury,pathology, condition, or disease.

A “therapeutically effective amount” or “effective amount” is an amountsufficient for a compound to accomplish a stated purpose relative to theabsence of the compound (e.g. achieve the effect for which it isadministered, treat a disease, reduce enzyme activity, increase enzymeactivity, reduce a signaling pathway, or reduce one or more symptoms ofa disease or condition). An example of an “effective amount” is anamount sufficient to contribute to the treatment, prevention, orreduction of a symptom or symptoms of a disease, which could also bereferred to as a “therapeutically effective amount.” A “reduction” of asymptom or symptoms (and grammatical equivalents of this phrase) meansdecreasing of the severity or frequency of the symptom(s), orelimination of the symptom(s). The exact amounts will depend on thepurpose of the treatment, and will be ascertainable by one skilled inthe art using known techniques (see, e.g., Lieberman, PharmaceuticalDosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technologyof Pharmaceutical Compounding (1999); Pickar, Dosage Calculations(1999); and Remington: The Science and Practice of Pharmacy, 20thEdition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

“Control” or “control experiment” is used in accordance with its plainordinary meaning and refers to an experiment in which the subjects orreagents of the experiment are treated as in a parallel experimentexcept for omission of a procedure, reagent, or variable of theexperiment. In some instances, the control is used as a standard ofcomparison in evaluating experimental effects. In some embodiments, acontrol is the measurement of the activity of a protein in the absenceof a compound as described herein (including embodiments and examples).

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” andthe like in reference to a protein-inhibitor interaction meansnegatively affecting (e.g. decreasing) the activity or function of theprotein relative to the activity or function of the protein in theabsence of the inhibitor. In some embodiments inhibition refers toreduction of a disease or symptoms of disease. In some embodiments,inhibition refers to a reduction in the activity of a particular proteinor nucleic acid target. Thus, inhibition includes, at least in part,partially or totally blocking stimulation, decreasing, preventing, ordelaying activation, or inactivating, desensitizing, or down-regulatingsignal transduction or enzymatic activity or the amount of a protein.

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated; however, the resulting reaction product can be produceddirectly from a reaction between the added reagents or from anintermediate from one or more of the added reagents which can beproduced in the reaction mixture.

The term “contacting” may include allowing two species to react,interact, or physically touch, wherein the two species may be a compoundas described herein and a protein or enzyme. In some embodimentscontacting includes allowing a compound described herein to interactwith a protein or enzyme that is involved in a signaling pathway.

“Patient,” “subject,” “patient in need thereof,” and “subject in needthereof” are herein used interchangeabley and refer to a living organismsuffering from or prone to a disease or condition that can be treated byadministration of a pharmaceutical composition as provided herein.Non-limiting examples include humans, other mammals, bovines, rats,mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammaliananimals. In some embodiments, a patient is human.

“Disease” or “condition” refer to a state of being or health status of apatient or subject capable of being treated with the compounds ormethods provided herein.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention. One of skill inthe art will recognize that other pharmaceutical excipients are usefulin the present invention.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

As used herein, the term “administering” means oral administration,administration as a suppository, topical contact, intravenous,parenteral, intraperitoneal, intramuscular, intralesional, intrathecal,intranasal or subcutaneous administration, or the implantation of aslow-release device, e.g., a mini-osmotic pump, to a subject.Administration is by any route, including parenteral and transmucosal(e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, ortransdermal). Parenteral administration includes, e.g., intravenous,intramuscular, intra-arteriole, intradermal, subcutaneous,intraperitoneal, intraventricular, and intracranial. Other modes ofdelivery include, but are not limited to, the use of liposomalformulations, intravenous infusion, transdermal patches, etc.

By “co-administer” it is meant that a composition described herein isadministered at the same time, just prior to, or just after theadministration of one or more additional therapies, for exampleepigenetic inhibitors or multi-kinase inhibitors. The compound of theinvention can be administered alone or can be co-administered to thepatient. Co-administration is meant to include simultaneous orsequential administration of the compound individually or in combination(more than one compound or agent). Thus, the preparations can also becombined, when desired, with other active substances (e.g. to reducemetabolic degradation).

The compositions disclosed herein can be delivered by transdermally, bya topical route, formulated as applicator sticks, solutions,suspensions, emulsions, gels, creams, ointments, pastes, jellies,paints, powders, and aerosols. Oral preparations include tablets, pills,powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups,slurries, suspensions, etc., suitable for ingestion by the patient.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. Liquid formpreparations include solutions, suspensions, and emulsions, for example,water or water/propylene glycol solutions. The compositions of thepresent invention may additionally include components to providesustained release and/or comfort. Such components include high molecularweight, anionic mucomimetic polymers, gelling polysaccharides andfinely-divided drug carrier substrates. These components are discussedin greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and4,861,760. The entire contents of these patents are incorporated hereinby reference in their entirety for all purposes. The compositionsdisclosed herein can also be delivered as microspheres for slow releasein the body. For example, microspheres can be administered viaintradermal injection of drug-containing microspheres, which slowlyrelease subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645,1995; as biodegradable and injectable gel formulations (see, e.g., GaoPharm. Res. 12:857-863, 1995); or, as microspheres for oraladministration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674,1997). In another embodiment, the formulations of the compositions ofthe present invention can be delivered by the use of liposomes whichfuse with the cellular membrane or are endocytosed, i.e., by employingreceptor ligands attached to the liposome, that bind to surface membraneprotein receptors of the cell resulting in endocytosis. By usingliposomes, particularly where the liposome surface carries receptorligands specific for target cells, or are otherwise preferentiallydirected to a specific organ, one can focus the delivery of thecompositions of the present invention into the target cells in vivo.(See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn,Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm.46:1576-1587, 1989). The compositions can also be delivered asnanoparticles.

Pharmaceutical compositions may include compositions wherein the activeingredient (e.g. compounds described herein, including embodiments orexamples) is contained in a therapeutically effective amount, i.e., inan amount effective to achieve its intended purpose. The actual amounteffective for a particular application will depend, inter alia, on thecondition being treated. When administered in methods to treat adisease, such compositions will contain an amount of active ingredienteffective to achieve the desired result, e.g., modulating the activityof a target molecule, and/or reducing, eliminating, or slowing theprogression of disease symptoms.

The dosage and frequency (single or multiple doses) administered to amammal can vary depending upon a variety of factors, for example,whether the mammal suffers from another disease, and its route ofadministration; size, age, sex, health, body weight, body mass index,and diet of the recipient; nature and extent of symptoms of the diseasebeing treated, kind of concurrent treatment, complications from thedisease being treated or other health-related problems. Othertherapeutic regimens or agents can be used in conjunction with themethods and compounds of Applicants' invention. Adjustment andmanipulation of established dosages (e.g., frequency and duration) arewell within the ability of those skilled in the art.

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached. Dosage amounts and intervals can be adjusted individually toprovide levels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

The term “associated” or “associated with” in the context of a substanceor substance activity or function associated with a disease means thatthe disease is caused by (in whole or in part), a symptom of the diseaseis caused by (in whole or inpart) the substance or substance activity orfunction, or a side-effect of the compound (e.g. toxicity) is caused by(in whole or inpart) the substance or substance activity or function.

As used herein, the term “cancer” refers to all types of cancer,neoplasm, or malignant tumors found in mammals, including leukemia,carcinomas and sarcomas. Exemplary cancers include acute myeloidleukemia (“AML”), chronic myelogenous leukemia (“CML”), and cancer ofthe brain, breast, pancreas, colon, liver, kidney, lung, non-small celllung, melanoma, ovary, sarcoma, and prostate. Additional examplesinclude, cervix cancers, stomach cancers, head & neck cancers, uteruscancers, mesothelioma, metastatic bone cancer, Medulloblastoma,Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma,neuroblastoma, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis,primary macroglobulinemia, primary brain tumors, cancer, malignantpancreatic insulanoma, malignant carcinoid, urinary bladder cancer,premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer,neuroblastoma, esophageal cancer, genitourinary tract cancer, malignanthypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms ofthe endocrine and exocrine pancreas, and prostate cancer.

The term “leukemia” refers broadly to progressive, malignant diseases ofthe blood-forming organs and is generally characterized by a distortedproliferation and development of leukocytes and their precursors in theblood and bone marrow. Leukemia is generally clinically classified onthe basis of (1) the duration and character of the disease-acute orchronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid(lymphogenous), or monocytic; and (3) the increase or non-increase inthe number abnormal cells in the blood-leukemic or aleukemic(subleukemic). The murine leukemia model is widely accepted as beingpredictive of in vivo anti-leukemic activity. It is believed that acompound that tests positive in the P388 cell assay will generallyexhibit some level of anti-leukemic activity regardless of the type ofleukemia being treated. Accordingly, the present invention includes amethod of treating leukemia, including treating acute myeloid leukemia,chronic lymphocytic leukemia, acute granulocytic leukemia, chronicgranulocytic leukemia, acute promyelocytic leukemia, adult T-cellleukemia, aleukemic leukemia, a leukocythemic leukemia, basophylicleukemia, blast cell leukemia, bovine leukemia, chronic myelocyticleukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia,Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia,hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia,acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia,lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia,megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia,myeloblastic leukemia, myelocytic leukemia, myeloid granulocyticleukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cellleukemia, multiple myeloma, plasmacytic leukemia, promyelocyticleukemia, Rieder cell leukemia, Schilling's leukemia, stem cellleukemia, subleukemic leukemia, and undifferentiated cell leukemia.

The term “sarcoma” generally refers to a tumor which is made up of asubstance like the embryonic connective tissue and is generally composedof closely packed cells embedded in a fibrillar or homogeneoussubstance. Sarcomas which can be treated with a combination ofantineoplastic thiol-binding mitochondrial oxidant and an anticanceragent include a chondrosarcoma, fibrosarcoma, lymphosarcoma,melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adiposesarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma,botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma,Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing'ssarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma,granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmentedhemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma,immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma,Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymomasarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma,serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma.

The term “melanoma” is taken to mean a tumor arising from themelanocytic system of the skin and other organs. Melanomas which can betreated with a combination of antineoplastic thiol-binding mitochondrialoxidant and an anticancer agent include, for example, acral-lentiginousmelanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman'smelanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma,lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungalmelanoma, and superficial spreading melanoma.

The term “carcinoma” refers to a malignant new growth made up ofepithelial cells tending to infiltrate the surrounding tissues and giverise to metastases. Exemplary carcinomas which can be treated with acombination of antineoplastic thiol-binding mitochondrial oxidant and ananticancer agent include, for example, acinar carcinoma, acinouscarcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinomaadenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolarcell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloidcarcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma,bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma,cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma,comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma encuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cellcarcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma,encephaloid carcinoma, epiermoid carcinoma, carcinoma epithelialeadenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum,gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma,carcinoma gigantocellulare, glandular carcinoma, granulosa cellcarcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellularcarcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypemephroidcarcinoma, infantile embryonal carcinoma, carcinoma in situ,intraepidermal carcinoma, intraepithelial carcinoma, Krompecher'scarcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticularcarcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelialcarcinoma, carcinoma medullare, medullary carcinoma, melanoticcarcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum,carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum,mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oatcell carcinoma, carcinoma ossificans, osteoid carcinoma, papillarycarcinoma, periportal carcinoma, preinvasive carcinoma, prickle cellcarcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reservecell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma,scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma,carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidalcell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamouscarcinoma, squamous cell carcinoma, string carcinoma, carcinomatelangiectaticum, carcinoma telangiectodes, transitional cell carcinoma,carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, andcarcinoma villosum.

Cancer model organism, as used herein, is an organism exhibiting aphenotype indicative of cancer, or the activity of cancer causingelements, within the organism. The term cancer is defined above. A widevariety of organisms may serve as cancer model organisms, and includefor example, cancer cells and mammalian organisms such as rodents (e.g.mouse or rat) and primates (such as humans). Cancer cell lines arewidely understood by those skilled in the art as cells exhibitingphenotypes or genotypes similar to in vivo cancers. Cancer cell lines asused herein includes cell lines from animals (e.g. mice) and fromhumans.

An “anticancer agent” as used herein refers to a molecule (e.g.compound, peptide, protein, nucleic acid, antibody) used to treat cancerthrough destruction or inhibition of cancer cells or tissues. Anticanceragents may be selective for certain cancers or certain tissues. Inembodiments, anticancer agents herein may include epigenetic inhibitorsand multi-kinase inhibitors.

An “epigenetic inhibitor” as used herein, refers to an inhibitor of anepigenetic process, such as DNA methylation (a DNA methylationInhibitor) or modification of histones (a Histone ModificationInhibitor). An epigenetic inhibitor may be a histone-deacetylase (HDAC)inhibitor, a DNA methyltransferase (DNMT) inhibitor, a histonemethyltransferase (HMT) inhibitor, a histone demethylase (HDM)inhibitor, or a histone acetyltransferase (HAT). Examples of HDACinhibitors include Vorinostat, romidepsin, CI-994, Belinostat,Panobinostat, Givinostat, Entinostat, Mocetinostat, SRT501, CUDC-101,JNJ-26481585, or PCI24781. Examples of DNMT inhibitors includeazacitidine and decitabine. Examples of HMT inhibitors include EPZ-5676.Examples of HDM inhibitors include pargyline and tranylcypromine.Examples of HAT inhibitors include CCT077791 and garcinol.

A “multi-kinase inhibitor” is a small molecule inhibitor of at least oneprotein kinase, including tyrosine protein kinases and serine/threoninekinases. A multi-kinase inhibitor may include a single kinase inhibitor.Multi-kinase inhibitors may block phosphorylation. Multi-kinasesinhibitors may act as covalent modifiers of protein kinases.Multi-kinase inhibitors may bind to the kinase active site or to asecondary or tertiary site inhibiting protein kinase activity. Amulti-kinase inhibitor may be an anti-cancer multi-kinase inhibitor.Exemplary anti-cancer multi-kinase inhibitors include dasatinib,sunitinib, erlotinib, bevacizumab, vatalanib, vemurafenib, vandetanib,cabozantinib, poatinib, axitinib, ruxolitinib, regorafenib, crizotinib,bosutinib, cetuximab, gefitinib, imatinib, lapatinib, lenvatinib,mubritinib, nilotinib, panitumumab, pazopanib, trastuzumab, orsorafenib.

“Selective” or “selectivity” or the like of a compound refers to thecompound's ability to discriminate between molecular targets (e.g. acompound having selectivity toward HMT SUV39H1 and/or HMT G9a).

“Specific”, “specifically”, “specificity”, or the like of a compoundrefers to the compound's ability to cause a particular action, such asinhibition, to a particular molecular target with minimal or no actionto other proteins in the cell (e.g. a compound having specificitytowards HMT SUV39H1 and/or HMT G9a displays inhibition of the activityof those HMTs whereas the same compound displays little-to-no inhibitionof other HMTs such as DOT1, EZH1, EZH2, GLP, MLL1, MLL2, MLL3, MLL4,NSD2, SET1b, SET7/9, SET8, SETMAR, SMYD2, SUV39H2).

“HMT SUV39H1,” “SUV39H1,” or “suppressor of varigation 3-9 homolgue 1”is a histone methyltransferase protein that trimethylates H3K9 (NCBI GINo. 49456451). HMT SUV39H1 may methylate H3K9.

“HMT G9a” or “G9a” is a histone methyltransferse that dimethylates H3K9(NCBI GI No. 287865). HMT G9a may dimethylate H3K9.

“H3K9 trimetylation” refers to tri-methylation of lysine 9 of HistoneH3. H3K9 trimethylation may be performed by histone methyl transferasessuch as SUV39H1.

Azacitidine is an epigenetic inhibitor having the formula:

including pharmaceutically acceptable salts thereof.

Azacitidine is an anti-cancer epigenetic inhibitor.

Decitadine is an epigenetic inhibitor having the formula:

including pharmaceutically acceptable salts thereof.

Decitadine is an anti-cancer epigenetic inhibitor.

Sorafenib is a multi-kinase inhibitor having the formula:

including pharmaceutically acceptable salts thereof.

Sorafenib is an anti-cancer multi-kinase inhibitor.

The terms “synergy”, “synergism” “synergistic” and “synergistictherapeutic effect” are used herein interchangeably and refer to ameasured effect of compounds administered in combination where themeasured effect is greater than the sum of the individual effects ofeach of the compounds administered alone as a single agent.

II. Compositions

In a first aspect is a compound having the formula:

The symbol p is 2, 3 or 4. R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33A), —NR^(34A)R^(35A), —COOR^(33A),—CONR^(34A)R^(35A), —NO₂, —SR^(36A), —SO_(n1)R^(34A), —SO_(n1)OR^(34A),—SO_(n1)NR^(34A)R^(35A), —NHNR^(34A)R^(35A), —ONR^(34A)R^(35A),—NHC(O)NHNR^(34A)R^(35A), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. R² ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33B),—NR^(34B)R^(35B), —COOR^(33B), —CONR^(34B)R^(35B), —NO₂, —SR^(36B),—SO_(n2)R^(34b), —SO_(n2)OR^(34B), —SO_(n2)NR^(34B)R^(35B),—NHNR^(34B)R^(35B), —ONR^(34B)R^(35B), —NHC(O)NHNR^(34B)R^(35B),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R³ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33C), —NR^(34C)R^(35C),—COOR^(33C), —CONR^(34C)R^(35C), —NO₂, —SR^(36C), —SO_(n3)R^(34C),—SO_(n3)OR^(34C), —SO_(n3)NR^(34C)R^(35C), —NHNR^(34C)R^(35C),—ONR^(34C)R^(35C), —NHC(O)NHNR^(34C)R^(35C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33D), —NR^(34D)R^(35D), —COOR^(33D),—CONR^(34D)R^(35D), —NO₂, —SR^(36D), —SO_(n4)R^(34D), —SO_(n4)OR^(34D),—NHNR^(34D)R^(35D), —ONR^(34D)R^(35D), —NHC(O)NHNR^(34D)R^(35D),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R⁵ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33E), —NR^(34E)R^(35E),—COOR^(33E), —CONR^(34E)R^(35E), —NO₂, —SR^(36E), —SO_(n5)R^(34E),—SO_(n5)OR^(34E), —SO_(n5)NR^(34E)R^(35E), —NHNR^(34E)R^(35E),—ONR^(34E)R^(35E), —NHC(O)NHNR^(34E)R^(35E), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33F), —NR^(34F)R^(35F), —COOR^(33F),—CONR^(34F)R^(35F), —NO₂, —SR^(36F), —SO_(n6)R^(34F), —SO_(n6)OR^(34F),—SO_(n6)NR^(34F)R^(35F), —NHNR^(34F)R^(35F), —ONR^(34F)R^(35F),—NHC(O)NHNR^(34F)R^(35F), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. R¹⁶is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(33G), —NR^(34G)R^(35G), —COOR^(33G), —CONR^(34G)R^(35G), —NO₂,—SR^(36G), —SO_(n7)R^(34G), —SO_(n7)OR^(34G), —SO_(n7)NR^(34G)R^(35G),—NHNR^(34G)R^(35G), —ONR^(34G)R^(35G), —NHC(O)NHNR^(34G)R^(35G),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R¹⁸ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33H), —NR^(34H)R^(35H),—COOR^(33H), —CONR^(34H)R^(35H), —NO₂, —SR^(36H), —SO_(n8)R^(34H),—SO_(n8)OR^(34H), —SO_(n8)NR^(34H)R^(35H), —NHNR^(34H)R^(35H),—ONR^(34H)R^(35H), —NHC(O)NHNR^(34H)R^(35H), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R^(33A), R^(34A), R^(35A), R^(36A), R^(33B),R^(34B), R^(35B), R^(36B), R^(33C), R^(34C), R^(35C), R^(36C), R^(33D),R^(34D), R^(35D), R^(36D), R^(33E), R^(34E), R^(35E), R^(36E), R^(33F),R^(34F), R^(35F), R^(36F), R^(33G), R^(34G), R^(35G), R^(36G), R^(33H),R^(34H), R^(35H), and R^(36H) are independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. The symbols n1, n2, n3, n4, n5, n6, n7, and n8are independently 1 or 2.

R^(33A), R^(34A), R^(35A), R^(36A), R^(33B), R^(34B), R^(35B), R^(36B),R^(33C), R^(34C), R^(35C), R^(36C), R^(33D), R^(34D), R^(35D), R^(36D),R^(33E), R^(34E), R^(35E), R^(36E), R^(33F), R^(34F), R^(35F), R^(36F),R^(33G), R^(34G), R^(35G), R^(36G), R^(33H), R^(34H), R^(35H), andR^(36H) may independently be hydrogen, unsubstituted alkyl,unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstitutedheterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

In embodiments, the compound may have the formula:

In embodiments, the compound may have the formula:

The symbol p may be 2. The symbol p may be 3. The symbol p may be 4.

R¹ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl), or substituted or unsubstituted heteroalkyl (e.g. 2 to 8membered heteroalkyl). R¹ may be halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,substituted or unsubstituted alkyl, or substituted or unsubstitutedheteroalkyl. R¹ may be —CN, substituted or unsubstituted alkyl, orsubstituted or unsubstituted heteroalkyl. R¹ may be —CN or substitutedor unsubstituted alkyl. R¹ may be —CN or unsubstituted alkyl. R¹ may be—CN, or unsubstituted heteroalkyl.

R¹ may be substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. R¹ maybe unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,unsubstituted heteroaryl, or unsubstituted membered heteroaryl.

R¹ may be substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted3 to 8 membered cycloalkyl, substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, substituted or unsubstituted 5 to 8 membered aryl, orsubstituted or unsubstituted 5 or 8 membered heteroaryl. R¹ may beunsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 membered heteroalkyl,unsubstituted 3 to 8 membered cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, unsubstituted 5 to 8 membered aryl, or unsubstituted 5or 8 membered heteroaryl.

R¹ may be substituted or unsubstituted C₁-C₅ alkyl, substituted orunsubstituted 2 to 5 membered heteroalkyl, substituted or unsubstituted3 to 5 membered cycloalkyl, substituted or unsubstituted 3-6 memberedheterocycloalkyl, substituted or unsubstituted 5 to 6 membered aryl, orsubstituted or unsubstituted 5 to 6 membered heteroaryl. R¹ may beunsubstituted C₁-C₅ alkyl, unsubstituted 2 to 5 membered heteroalkyl,unsubstituted 3 to 5 membered cycloalkyl, unsubstituted 3-6 memberedheterocycloalkyl, unsubstituted 5 to 6 membered aryl, or unsubstituted 5to 6 membered heteroaryl.

R¹ may be substituted or unsubstituted C₁-C₃ alkyl, substituted orunsubstituted 2 to 3 membered heteroalkyl. R¹ may be substituted orunsubstituted 3 membered cycloalkyl, substituted or unsubstituted 4membered cycloalkyl, or substituted or unsubstituted 5 memberedcycloalkyl. R¹ may be substituted or unsubstituted 4 memberedheterocycloalkyl, substituted or unsubstituted 5 memberedheterocycloalkyl, or substituted or unsubstituted 6 memberedheterocycloalkyl. R¹ may be substituted or unsubstituted 5 memberedaryl, substituted or unsubstituted 5 membered aryl, substituted orunsubstituted 6 membered aryl, or substituted or unsubstituted 6membered heteroaryl. R¹ may be unsubstituted C₁-C₃ alkyl orunsubstituted 2 to 3 membered heteroalkyl. R¹ may be unsubstituted 3membered cycloalkyl, unsubstituted 4 membered cycloalkyl orunsubstituted membered cycloalkyl. R¹ may be unsubstituted 4 memberedheterocycloalkyl, unsubstituted 5 membered heterocycloalkyl, orunsubstituted 6 membered heterocycloalkyl. R¹ may be unsubstituted 5membered aryl, unsubstituted 5 membered aryl, unsubstituted 6 memberedaryl, or unsubstituted 6 membered heteroaryl.

R¹ may be R^(1a)-substituted or unsubstituted alkyl, R^(1a)-substitutedor unsubstituted heteroalkyl, R^(1a)-substituted or unsubstitutedcycloalkyl, R^(1a)-substituted or unsubstituted heterocycloalkyl,R^(1a)-substituted or unsubstituted aryl, or R^(1a)-substituted orunsubstituted heteroaryl. R¹ may be unsubstituted alkyl, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, or unsubstituted heteroaryl.

R¹ may be R^(1a)-substituted or unsubstituted C₁-C₈ alkyl,R^(1a)-substituted or unsubstituted 2 to 8 membered heteroalkyl,R^(1a)-substituted or unsubstituted 3 to 8 membered cycloalkyl,R^(1a)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(1a)-substituted or unsubstituted 5 to 8 membered aryl, orR^(1a)-substituted or unsubstituted 5 to 8 membered heteroaryl. R¹ maybe unsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 membered heteroalkyl,unsubstituted 3 to 8 membered cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, unsubstituted 5 to 8 membered aryl, or unsubstituted 5to 8 membered heteroaryl.

R¹ may be R^(1a)-substituted or unsubstituted C₁-C₅ alkyl,R^(1a)-substituted or unsubstituted 2 to 5 membered heteroalkyl,R^(1a)-substituted or unsubstituted 3 to 5 membered cycloalkyl,R^(1a)-substituted or unsubstituted 3-6 membered heterocycloalkyl,R^(1a)-substituted or unsubstituted 5 to 6 membered aryl, orR^(1a)-substituted or unsubstituted 5 to 6 membered heteroaryl. R¹ maybe unsubstituted C₁-C₅ alkyl, unsubstituted 2 to 5 membered heteroalkyl,unsubstituted 3 to 5 membered cycloalkyl, unsubstituted 3 to 6 memberedheterocycloalkyl, or unsubstituted 5 to 6 membered aryl, orunsubstituted 5 to 6 membered heteroaryl.

R¹ may be R^(1a)-substituted or unsubstituted C₁-C₃ alkyl orR^(1a)-substituted or unsubstituted 2 to 3 membered heteroalkyl. R¹ maybe R^(1a)-substituted or unsubstituted 3 membered cycloalkyl,R^(1a)-substituted or unsubstituted 4 membered cycloalkyl, orR^(1a)-substituted or unsubstituted 5 membered cycloalkyl. R¹ may beR^(1a)-substituted or unsubstituted 5 membered heterocycloalkyl,R^(a)-substituted or unsubstituted 6 membered heterocycloalkyl,R^(1a)-substituted or unsubstituted 5 membered aryl, R^(1a)-substitutedor unsubstituted 6 membered aryl, R^(1a)-substituted or unsubstituted 5membered heteroaryl, or R^(1a)-substituted or unsubstituted 6 memberedheteroaryl. R¹ may be unsubstituted C₁-C₃ alkyl or unsubstituted 2 to 3membered heteroalkyl. R¹ may be unsubstituted 3 membered cycloalkyl,unsubstituted 4 membered cycloalkyl, unsubstituted 5 memberedcycloalkyl, unsubstituted 5 membered heterocycloalkyl, unsubstituted 6membered heterocycloalkyl, unsubstituted 5 membered aryl, unsubstituted6 membered aryl, unsubstituted 5 membered heteroaryl, or unsubstituted 6membered heteroaryl.

R¹ may be R^(1a)-substituted or unsubstituted methyl, R^(1a)-substitutedor unsubstituted ethyl, or R^(1a)-substituted or unsubstituted propyl.R¹ may be methyl, ethyl, or propyl.

R¹ may be halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, NO₂,or —COOR^(33A). R^(33A) may be hydrogen, C₁-C₃ unsubstituted alkyl, 2 to5 membered unsubstituted heteroalkyl, or 5 or 6 membered unsubstitutedaryl. In embodiments, R¹ is —COOR^(33A), wherein R^(33A) is C₁-C₃unsubstituted alkyl. R³³ may be unsubstituted methyl, unsubstitutedethyl, or unsubstituted propyl. R¹ may be —COOCH₃. R¹ may be halogen,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —NH₂, or NO₂. R¹ may be —CN. R¹ may beunsubstituted 2 to 5 membered heteroalkyl.

R^(1a) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, R^(1b)-substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl), R^(1b)-substituted or unsubstituted heteroalkyl (e.g. 2 to 8membered heteroalkyl), R^(1b)-substituted or unsubstituted cycloalkyl(e.g. C₃-C₈ cycloalkyl), R^(1b)-substituted or unsubstitutedheterocycloalkyl (e.g. 3 to 6 membered heterocycloalkyl),R^(1b)-substituted or unsubstituted aryl (e.g. 5 or 6 membered aryl), orR^(1b)-substituted or unsubstituted heteroaryl (e.g. 5 or 6 memberedheteroaryl).

R^(1b) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, unsubstituted alkyl (e.g. C₁-C₈ alkyl), heteroalkyl (e.g.2 to 8 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 6 memberedheterocycloalkyl), unsubstituted aryl (e.g. 5 or 6 membered aryl), orunsubstituted heteroaryl (e.g. 5 or 6 membered heteroaryl).

R¹ may be an electron withdrawing group (EWG) (e.g. halogen, —N₃, —NO₂,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —CONH₂, or substituted orunsubstituted 2 to 8 membered heteroalkyl). An “electron withdrawinggroup” is used herein according to its common meaning in the art andrefers to a chemical moiety that tends to remove electrons (electrondensity) from a portion of the compound to which it is attached (e.g. adeactivating group). R¹ may be —CN. R¹ may be —NO₂. R¹ may be —CF₃,—CCl₃, —CBr₃, or —CI₃. R¹ may be substituted or unsubstituted 2 to 8membered heteroalkyl. R¹ may be —COOCH₃.

R² may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl), or substituted or unsubstituted heteroalkyl (e.g. 2 to 8membered heteroalkyl), or substituted or unsubstituted heterocycloalkyl(e.g. 3 to 6 membered heterocycloalkyl). R² may be halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl. R² may be —CN, substituted or unsubstitutedalkyl, or substituted or unsubstituted heteroalkyl. R² may be —CN orsubstituted or unsubstituted alkyl. R² may be —CN or unsubstitutedmethyl. R² may be —CN, or unsubstituted heteroalkyl. R² may besubstituted alkyl or substituted heteroalkyl.

R² may be substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. R² maybe unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, orunsubstituted heteroaryl.

R² may be substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted3 to 8 membered cycloalkyl, substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, substituted or unsubstituted 5 or 8 membered aryl, orsubstituted or unsubstituted 5 or 8 membered heteroaryl. R² may beunsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 membered heteroalkyl,unsubstituted 3 to 8 membered cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, unsubstituted 5 or 8 membered aryl, or unsubstituted 5or 8 membered heteroaryl.

R² may be substituted or unsubstituted C₁-C₅ alkyl, substituted orunsubstituted 2 to 5 membered heteroalkyl, substituted or unsubstituted3 to 5 membered cycloalkyl, or substituted or unsubstituted 3 to 6membered heterocycloalkyl, substituted or unsubstituted 5 or 6 memberedaryl, or substituted or unsubstituted 5 or 6 membered heteroaryl. R² maybe unsubstituted C₁-C₅ alkyl, unsubstituted 2 to 5 membered heteroalkyl,unsubstituted 3 to 5 membered cycloalkyl, or unsubstituted 3 to 6membered heterocycloalkyl, unsubstituted 5 or 6 membered aryl, orunsubstituted 5 or 6 membered heteroaryl. R² may be unsubstituted C₁-C₅alkyl or unsubstituted 2 to 5 membered heteroalkyl.

R² may be substituted or unsubstituted C₁-C₃ alkyl or substituted orunsubstituted 2 to 3 membered heteroalkyl. R² may be substituted orunsubstituted 3 membered cycloalkyl, substituted or unsubstituted 4membered cycloalkyl, or substituted or unsubstituted 5 memberedcycloalkyl. R² may be substituted or unsubstituted 4 memberedheterocycloalkyl, substituted or unsubstituted 5 memberedheterocycloalkyl, substituted or unsubstituted 6 memberedheterocycloalkyl, substituted or unsubstituted 5 membered aryl,substituted or unsubstituted 6 membered aryl, substituted orunsubstituted 5 membered heteroaryl, or substituted or unsubstituted 6membered heteroaryl. R² may be unsubstituted C₁-C₃ alkyl orunsubstituted 2 to 3 membered heteroalkyl. R² may be unsubstituted 3membered cycloalkyl, unsubstituted 4 membered cycloalkyl orunsubstituted 5 membered cycloalkyl. R² may be unsubstituted 4 memberedheterocycloalkyl, unsubstituted 5 membered heterocycloalkyl,unsubstituted 6 membered heterocycloalkyl, unsubstituted 5 memberedaryl, unsubstituted 6 membered aryl, unsubstituted 5 memberedheteroaryl, or unsubstituted 6 membered heteroaryl.

R² may be R^(2a)-substituted or unsubstituted alkyl, R^(2a)-substitutedor unsubstituted heteroalkyl, R^(2a)-substituted or unsubstitutedcycloalkyl, R^(2a)-substituted or unsubstituted heterocycloalkyl,R^(2a)-substituted or unsubstituted aryl, or R^(2a)-substituted orunsubstituted heteroaryl. R² may be R^(2a)-substituted or unsubstitutedalkyl or R^(2a)-substituted or unsubstituted heteroalkyl.

R² may be R^(2a)-substituted or unsubstituted C₁-C₈ alkyl,R^(2a)-substituted or unsubstituted 2 to 8 membered heteroalkyl,R^(2a)-substituted or unsubstituted 3 to 8 membered cycloalkyl,R^(2a)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(2a)-substituted or unsubstituted 5 or 8 membered aryl, orR^(2a)-substituted or unsubstituted 5 or 8 membered heteroaryl. R² maybe R^(2a)-substituted or unsubstituted C₁-C₈ alkyl or R^(2a)-substitutedor unsubstituted 2 to 8 membered heteroalkyl, R^(2a)-substituted orunsubstituted 3 to 8 membered cycloalkyl, R^(2a)-substituted orunsubstituted 3 to 8 membered heterocycloalkyl, R^(2a)-substituted orunsubstituted 5 to 8 membered aryl, or R^(2a)-substituted orunsubstituted 5 to 8 membered heteroaryl.

R² may be R^(2a)-substituted or unsubstituted C₁-C₅ alkyl,R^(2a)-substituted or unsubstituted 2 to 5 membered heteroalkyl,R^(2a)-substituted or unsubstituted 3 to 5 membered cycloalkyl,R^(2a)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(2a)-substituted or unsubstituted 5 or 6 membered aryl, orR^(2a)-substituted or unsubstituted 5 to 6 membered heteroaryl. R² maybe R^(2a)-substituted or unsubstituted C₁-C₅ alkyl or R^(2a)-substitutedor unsubstituted 2 to 5 membered heteroalkyl.

R² may be R^(2a)-substituted or unsubstituted C₁-C₃ alkyl orR^(2a)-substituted or unsubstituted 2 to 3 membered heteroalkyl. R² maybe R^(2a)-substituted or unsubstituted 3 membered cycloalkyl,R^(2a)-substituted or unsubstituted 4 membered cycloalkyl, orR^(2a)-substituted or unsubstituted 5 membered cycloalkyl. R² may beR^(2a)-substituted or unsubstituted 4 membered heterocycloalkyl,R^(2a)-substituted or unsubstituted 5 membered heterocycloalkyl,R^(2a)-substituted or unsubstituted 6 membered heterocycloalkyl,R^(2a)-substituted or unsubstituted 5 membered aryl, R^(2a)-substitutedor unsubstituted 6 membered aryl, R^(2a)-substituted or unsubstituted 5membered heteroaryl, or R^(2a)-substituted or unsubstituted 6 memberedheteroaryl.

R^(2a) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, R^(2b)-substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl), R^(2b)-substituted or unsubstituted heteroalkyl (e.g. 2 to 8membered heteroalkyl), R^(2b)-substituted or unsubstituted cycloalkyl(e.g. 3 to 8 membered cycloalkyl), R^(2b)-substituted or unsubstitutedheterocycloalkyl (e.g. 3 to 6 membered heterocycloalkyl),R^(2b)-substituted or unsubstituted aryl (e.g. 5 or 6 membered aryl), orR^(2b)-substituted or unsubstituted heteroaryl (e.g. 5 or 6 memberedheteroaryl). R^(2a) may be 3 to 6 membered heterocycloalkyl,R^(2b)-substituted or unsubstituted 5 or 6 membered aryl, orR^(2b)-substituted or unsubstituted 5 or 6 membered heteroaryl. R^(2a)may be unsubstituted pyridine. R^(2a) may be unsubstituted morpholino.R^(2a) may be unsubstituted methyl.

R^(2b) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, unsubstituted alkyl (e.g. C₁-C₈ alkyl), unsubstitutedheteroalkyl (e.g. 2 to 8 membered heteroalkyl), unsubstituted cycloalkyl(e.g. 3 to 8 membered cycloalkyl), unsubstituted heterocycloalkyl (e.g.3 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g. 5 or 6membered aryl), or unsubstituted heteroaryl (e.g. 5 or 6 memberedheteroaryl).

R² may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, R^(2a)-substituted or unsubstituted C₁-C₈alkyl, R^(2a)-substituted or unsubstituted 2 to 8 membered heteroalkyl,R^(2a)-substituted or unsubstituted 3 to 8 membered cycloalkyl,R^(2a)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(2a)-substituted or unsubstituted 5 or 6 membered aryl, orR^(2a)-substituted or unsubstituted 5 or 6 membered heteroaryl. R² maybe —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂Ph, —SO₂NH₂, —NHNH₂, —ONH₂,R^(2a)-substituted or unsubstituted C₁-C₃ alkyl, or 1 to 3 memberedR^(2a)-substituted or unsubstituted heteroalkyl. In embodiments R² isunsubstituted C₁-C₅ alkyl or unsubstituted 2 to 5 membered heteroalkyl.In embodiments R² is unsubstituted methyl. In embodiments R² isunsubstituted methoxy (e.g. —OCH₃).

R² may be R^(2a)-substituted or unsubstituted C₁-C₅ alkyl (e.g.R^(2a)-substituted or unsubstituted methylene). R² may beR^(2a)-substituted C₁-C₅ alkyl. When R² is substituted or unsubstitutedC₁-C₅ alkyl, R^(2a) may be unsubstituted heterocycloalkyl, unsubstitutedaryl, or unsubstituted heteroaryl. R^(2a) may be unsubstituted orunsubstituted morpholino (e.g. R^(2b)-substituted or unsubstitutedmorpholino). R² may be R^(2a)-substituted or unsubstituted 2 to 5membered heteroalkyl. When R² is substituted or unsubstituted 2 to 5membered heteroalkyl, R^(2a) may be may be unsubstituted C₁-C₅ alkyl,unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstitutedheteroaryl. R² may be —OCH₃. R² may be unsubstituted methyl. R² may be—CN.

In embodiments, R¹ is halogen, —N₃, —NO₂, —CF₃, CCl₃, CBr₃, CI₃, —CN,—CHO, —CONH₂, or substituted or unsubstituted 2 to 8 memberedheteroalkyl and R² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, R^(2a)-substituted orunsubstituted C₁-C₅ alkyl, R^(2a)-substituted or unsubstituted 2 to 8membered heteroalkyl, R^(2a)-substituted or unsubstituted 3 to 8membered cycloalkyl, R^(2a)-substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, R^(2a)-substituted or unsubstituted 5 or 6 memberedaryl, or R^(2a)-substituted or unsubstituted 5 or 6 membered heteroarylheteroaryl. In embodiments, at least one of R¹ and R² is an electronwithdrawing group (EWG) (e.g. halogen, —N₃, —NO₂, —CF₃, CCl₃, CBr₃, CI₃,—CN, —CHO, —CONH₂, or substituted or unsubstituted 3 to 8 memberedheteroalkyl. When R¹ is CN, R² may be —CN. When R¹ is halogen, R² may behalogen. When R¹ is —CN, R² may be unsubstituted C₁-C₅ alkyl. When R¹ is—CN, R² may be unsubstituted methyl. When R¹ is unsubstituted 2 to 8membered heteroalkyl (e.g. —COOCH₃), R² may be may be unsubstitutedC₁-C₅ alkyl. When R¹ is —CN, R² may be R^(2a)-substituted orunsubstituted C₁-C₅ alkyl. When R¹ is —CN, R² may be R^(2a)-substitutedor unsubstituted C₁-C₅ heteroalkyl. R^(2a) may be unsubstituted alkyl,unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstitutedaryl, or unsubstituted heteroaryl.

In embodiments, R² is a polar substituent and provides polarity to thecompounds provided herein (e.g. where R² is a substituted orunsubstituted 2 to 8 membered heteroalkyl). A “polar substituent” isunderstood by one skilled in the art to be a moiety that creates adipole moment, thereby forming a positive or negative charge on amolecule. R² may be an aqueous solubility enhancing substituent (e.g. amoiety that increases the water solubility of the compound), wheregerminal substitution at R² with a substituent other than methylimproves the solubility of the compound in an aqueous medium. Solubilityenhancing substituents may include basic substituents or groups that addpolarity.

R³ and R⁴ may independently be substituted or unsubstituted heteroalkyl,substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted orunsubstituted 2 to 5 membered heteroalkyl, substituted or unsubstituted2 to 3 membered heteroalkyl, R^(30a)-substituted or unsubstitutedheteroalkyl, R^(30a)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(30a)-substituted or unsubstituted 2 to 5 memberedheteroalkyl, or R^(30a)-substituted or unsubstituted 2 to 3 memberedheteroalkyl. R³ and R⁴ may independently be unsubstituted heteroalkyl,unsubstituted 2 to 8 membered heteroalkyl, or unsubstituted 2 to 5membered heteroalkyl, unsubstituted 2 to 3 membered heteroalkyl.

R³ and R⁴ may independently be substituted or unsubstituted cycloalkyl,substituted or unsubstituted 3 to 8 membered cycloalkyl, substituted orunsubstituted 3 to 5 membered cycloalkyl, substituted or unsubstituted 3membered cycloalkyl, substituted or unsubstituted 4 membered cycloalkyl,substituted or unsubstituted 5 membered cycloalkyl. R³ and R⁴ mayindependently be R^(30a)-substituted or unsubstituted cycloalkyl,R^(30a)-substituted or unsubstituted 3 to 8 membered cycloalkyl,R^(30a)-substituted or unsubstituted 3 to 5 membered cycloalkyl,R^(30a)-substituted or unsubstituted 3 membered cycloalkyl,R^(30a)-substituted or unsubstituted 4 membered cycloalkyl, orR^(30a)-substituted or unsubstituted 5 membered cycloalkyl.

R³ and R⁴ may independently be substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted 4 memberedheterocycloalkyl, substituted or unsubstituted 5 memberedheterocycloalkyl, substituted or unsubstituted 6 memberedheterocycloalkyl. R³ and R⁴ may independently be R^(30a)-substituted orunsubstituted heterocycloalkyl, R^(30a)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(30a)-substituted or unsubstituted 4membered heterocycloalkyl, R^(30a)-substituted or unsubstituted 5membered heterocycloalkyl, or R^(30a)-substituted or unsubstituted 6membered heterocycloalkyl.

R³ and R⁴ may independently be substituted or unsubstituted aryl,substituted or unsubstituted 5 to 6 membered aryl, substituted orunsubstituted 5 membered aryl, or substituted or unsubstituted 6membered aryl. R³ and R⁴ may independently be R^(30a)-substituted orunsubstituted aryl, R^(30a)-substituted or unsubstituted 5 to 6 memberedaryl, R^(30a)-substituted or unsubstituted 5 membered aryl, orR^(30a)-substituted or unsubstituted 6 membered aryl. R³ and R⁴ mayindependently be substituted or unsubstituted heteroaryl, substituted orunsubstituted 5 to 6 membered heteroaryl, substituted or unsubstituted 5membered heteroaryl, or substituted or unsubstituted 6 memberedheteroaryl. R³ and R⁴ may independently be R^(30a)-substituted orunsubstituted heteroaryl, R^(30a)-substituted or unsubstituted 5 to 6membered heteroaryl, R^(30a)-substituted or unsubstituted 5 memberedheteroaryl, or R^(30a)-substituted or unsubstituted 6 memberedheteroaryl.

R³ may be hydrogen, halogen, or R^(30a)-substituted or unsubstitutedC₁-C₈ alkyl. R³ may be hydrogen. R³ may be unsubstituted methyl,unsubstituted ethyl, or unsubstituted propyl.

R⁴ may be hydrogen, halogen, or R^(30a)-substituted or unsubstitutedC₁₋₈ alkyl. R⁴ may be hydrogen. R⁴ may be unsubstituted methyl,unsubstituted ethyl, or unsubstituted propyl. In embodiments, R³ and R⁴are hydrogen.

R^(30a) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, R^(30b)-substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl), R^(30b)-substituted or unsubstituted heteroalkyl (e.g. 2 to 8membered heteroalkyl), R^(30b)-substituted or unsubstituted cycloalkyl(e.g. 3 to 8 membered cycloalkyl), R^(30b)-substituted or unsubstitutedheterocycloalkyl (e.g. 3 to 6 membered heterocycloalkyl),R^(30b)-substituted or unsubstituted aryl (e.g. 5 to 6 membered aryl),or R^(30b)-substituted or unsubstituted heteroaryl (e.g. 5 to 6 memberedheteroaryl).

R^(30b) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, unsubstituted alkyl (e.g. C₁-C₈ alkyl), unsubstitutedheteroalkyl (e.g. 2 to 8 membered heteroalkyl), unsubstituted cycloalkyl(e.g. 3 to 8 membered cycloalkyl), unsubstituted heterocycloalkyl (e.g.3 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g. 5 to 6membered aryl), or unsubstituted heteroaryl (e.g. 5 to 6 memberedheteroaryl).

R⁵ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂. R⁵ may be halogen, —CHO, —COOH, —CONH₂,—SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl(e.g. C₁-C₅ alkyl), or substituted or unsubstituted heteroalkyl (e.g. 2to 6 membered heteroalkyl). R⁵ may be halogen, —CHO, —COOH, —CONH₂, —SH,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, R^(5a)-substituted or unsubstituted alkyl(e.g. C₁-C₅ alkyl), or R^(5a)-substituted or unsubstituted heteroalkyl(e.g. 2 to 6 membered heteroalkyl).

R⁵ may be substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. R⁵ maybe unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, orunsubstituted heteroaryl.

R⁵ may be substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted3 to 8 membered cycloalkyl, substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, or substituted or unsubstituted 5 to 8 membered aryl,or substituted or unsubstituted 5 to 8 membered heteroaryl. R⁵ may beunsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 membered heteroalkyl,unsubstituted 3 to 8 membered cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, or unsubstituted 5 to 8 membered aryl, orunsubstituted 5 to 8 membered heteroaryl.

R⁵ may be substituted or unsubstituted C₁-C₅ alkyl, substituted orunsubstituted 2 to 5 membered heteroalkyl, substituted or unsubstituted3 to 5 membered cycloalkyl, or be substituted or unsubstituted 3 to 6membered heterocycloalkyl, substituted or unsubstituted 5 to 6 memberedaryl, or substituted or unsubstituted 5 to 6 membered heteroaryl. R⁵ maybe unsubstituted C₁-C₅ alkyl, unsubstituted 2 to 5 membered heteroalkyl,unsubstituted 3 to 5 membered cycloalkyl, unsubstituted 3 to 6 memberedheterocycloalkyl, unsubstituted 5 to 6 membered aryl, or unsubstituted 5to 6 membered heteroaryl.

R⁵ may be substituted or unsubstituted C₁-C₃ alkyl or substituted orunsubstituted 2 to 3 membered heteroalkyl. R⁵ may be substituted orunsubstituted 3 membered cycloalkyl. R⁵ may be substituted orunsubstituted 4 membered cycloalkyl or substituted or unsubstituted 5membered cycloalkyl. R⁵ may be substituted or unsubstituted 4 memberedheterocycloalkyl, substituted or unsubstituted 5 memberedheterocycloalkyl, substituted or unsubstituted 6 memberedheterocycloalkyl. R⁵ may be substituted or unsubstituted 5 memberedaryl, substituted or unsubstituted 6 membered aryl, substituted orunsubstituted 5 membered heteroaryl, or substituted or unsubstituted 6membered heteroaryl. R⁵ may be unsubstituted C₁-C₃ alkyl orunsubstituted 2 to 3 membered heteroalkyl. R⁵ may be unsubstituted 3membered cycloalkyl. R⁵ may be unsubstituted 4 membered cycloalkyl orunsubstituted 5 membered cycloalkyl. R⁵ may be unsubstituted 4 memberedheterocycloalkyl, unsubstituted 5 membered heterocycloalkyl,unsubstituted 6 membered heterocycloalkyl. R⁵ may be unsubstituted 5membered aryl, unsubstituted 6 membered aryl, unsubstituted 5 memberedheteroaryl, or unsubstituted 6 membered heteroaryl.

R⁵ may be R^(5a)-substituted or unsubstituted alkyl, R^(5a)-substitutedor unsubstituted heteroalkyl, R^(5a)-substituted or unsubstitutedcycloalkyl, R^(5a)-substituted or unsubstituted heterocycloalkyl,R^(5a)-substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R⁵ may be unsubstituted alkyl, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R⁵ may be R^(5a)-substituted or unsubstituted C₁-C₈ alkyl,R^(5a)-substituted or unsubstituted 3 to 8 membered heteroalkyl,R^(5a)-substituted or unsubstituted 3 to 8 membered cycloalkyl,R^(5a)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(5a)-substituted or unsubstituted 5 to 8 membered aryl, orR^(5a)-substituted or unsubstituted 5 to 8 membered heteroaryl. R⁵ maybe unsubstituted C₁-C₈ alkyl, unsubstituted 3 to 8 membered heteroalkyl,unsubstituted 3 to 8 membered cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, unsubstituted 5 to 8 membered aryl, or unsubstituted 5to 8 membered heteroaryl.

R⁵ may be R^(5a)-substituted or unsubstituted C₁-C₅ alkyl,R^(5a)-substituted or unsubstituted 2 to 5 membered heteroalkyl,R^(5a)-substituted or unsubstituted 3 to 5 membered cycloalkyl,R^(5a)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(5a)-substituted or unsubstituted 5 to 6 membered aryl, orR^(5a)-substituted or unsubstituted 5 to 6 membered heteroaryl. R⁵ maybe unsubstituted C₁-C₅ alkyl, unsubstituted 2 to 5 membered heteroalkyl,unsubstituted 3 to 5 membered cycloalkyl, unsubstituted 3 to 6 memberedheterocycloalkyl, unsubstituted 5 to 6 membered aryl, or orunsubstituted 5 to 6 membered heteroaryl.

R⁵ may be R^(5a)-substituted or unsubstituted C₁-C₃ alkyl orR^(5a)-substituted or unsubstituted 2 to 3 membered heteroalkyl. R⁵ maybe R^(5a)-substituted or unsubstituted 3 membered cycloalkyl,R^(5a)-substituted or unsubstituted 4 membered cycloalkyl, orR^(5a)-substituted or unsubstituted 5 membered cycloalkyl. R⁵ may beR^(5a)-substituted or unsubstituted 4 membered heterocycloalkyl,R^(5a)-substituted or unsubstituted 5 membered heterocycloalkyl, orR^(5a)-substituted or unsubstituted 6 membered heterocycloalkyl. R⁵ maybe R^(5a)-substituted or unsubstituted 5 membered aryl,R^(5a)-substituted or unsubstituted 6 membered aryl, R^(5a)-substitutedor unsubstituted 5 membered heteroaryl, or R^(5a)-substituted orunsubstituted 6 membered heteroaryl. R⁵ may be unsubstituted C₁-C₃ alkylor or unsubstituted 2 to 3 membered heteroalkyl. R⁵ may be orunsubstituted 3 membered cycloalkyl, or unsubstituted 4 memberedcycloalkyl, or or unsubstituted 5 membered cycloalkyl. R⁵ may be orunsubstituted 4 membered heterocycloalkyl, or unsubstituted 5 memberedheterocycloalkyl, or or unsubstituted 6 membered heterocycloalkyl. R⁵may be or unsubstituted 5 membered aryl, or unsubstituted 6 memberedaryl, or unsubstituted 5 membered heteroaryl, or or unsubstituted 6membered heteroaryl.

R^(5a) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, R^(5b)-substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl), R^(5b)-substituted or unsubstituted heteroalkyl (e.g. 2 to 8membered heteroalkyl), R^(5b)-substituted or unsubstituted cycloalkyl(e.g. 3 to 8 membered cycloalkyl), R^(5b)-substituted or unsubstitutedheterocycloalkyl (e.g. 3 to 6 membered heterocycloalkyl),R^(5b)-substituted or unsubstituted aryl (e.g. 5 to 6 membered aryl), orR^(5b)-substituted or unsubstituted heteroaryl (e.g. 5 to 6 memberedheteroaryl).

R^(5b) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, unsubstituted alkyl (e.g. C₁-C₈ alkyl), unsubstitutedheteroalkyl (e.g. 2 to 8 membered heteroalkyl), unsubstituted cycloalkyl(e.g. 3 to 8 membered cycloalkyl), unsubstituted heterocycloalkyl (e.g.3 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g. 5 to 6membered aryl), or unsubstituted heteroaryl (e.g. 5 to 6 memberedheteroaryl).

R⁵ may be R^(5a)-substituted or unsubstituted C₁-C₈ alkyl,R^(5a)-substituted or unsubstituted 2 to 8 membered heteroalkyl,unsubstituted 3 to 5 membered cycloalkyl, or unsubstituted 3 to 5membered heterocycloalkyl. R⁵ may be unsubstituted C₁-C₈ alkyl. R⁵ maybe unsubstituted methyl, unsubstituted ethyl, or unsubstituted propyl.R⁵ may be methyl, ethyl, or propyl. R⁵ may be unsubstituted methyl. R⁵may be unsubstituted ethyl. R⁵ may be unsubstituted propyl. R⁵ may beunsubstituted allyl. R⁵ may be R^(5a)-substituted alkyl. R^(5a) may beunsubstituted 5 or 6 membered heterocycloalkyl. R^(5a) may beunsubstituted morpholino. In embodiments, R⁵ is substituted orunsubstituted 2 to 8 membered heteroalkyl. R⁵ may be —(CH₂)₃N(CH₃)₃. R⁵may be unsubstituted 3 to 5 membered cycloalkyl. In embodiments, R⁵ isunsubstituted cyclopropane.

R⁶ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂. R⁶ may be hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, orsubstituted or unsubstituted alkyl (e.g. C₁-C₅ alkyl), or substituted orunsubstituted heteroalkyl (e.g. 2 to 6 membered heteroalkyl). R⁶ may behalogen, —CHO, —COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,R^(6a)-substituted or unsubstituted alkyl (e.g. C₁-C₅ alkyl), orR^(6a)-substituted or unsubstituted heteroalkyl (e.g. 2 to 6 memberedheteroalkyl).

R⁶ may be substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. R⁶ maybe unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, orunsubstituted heteroaryl.

R⁶ may be substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted3 to 8 membered cycloalkyl, substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, or substituted or unsubstituted 5 to 8 membered aryl,or substituted or unsubstituted 5 to 8 membered heteroaryl. R⁶ may beunsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 membered heteroalkyl,unsubstituted 3 to 8 membered cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, or unsubstituted 5 to 8 membered aryl, orunsubstituted 5 to 8 membered heteroaryl.

R⁶ may be substituted or unsubstituted C₁-C₅ alkyl, substituted orunsubstituted 2 to 5 membered heteroalkyl, substituted or unsubstituted3 to 5 membered cycloalkyl, or be substituted or unsubstituted 3 to 6membered heterocycloalkyl, substituted or unsubstituted 5 to 6 memberedaryl, or substituted or unsubstituted 5 to 6 membered heteroaryl. R⁶ maybe unsubstituted C₁-C₅ alkyl, unsubstituted 2 to 5 membered heteroalkyl,unsubstituted 3 to 5 membered cycloalkyl, or be unsubstituted 3 to 6membered heterocycloalkyl, unsubstituted 5 to 6 membered aryl, orunsubstituted 5 to 6 membered heteroaryl.

R⁶ may be substituted or unsubstituted C₁-C₃ alkyl or substituted orunsubstituted 2 to 3 membered heteroalkyl. R⁶ may be substituted orunsubstituted 3 membered cycloalkyl, substituted or unsubstituted 4membered cycloalkyl, or substituted or unsubstituted 5 memberedcycloalkyl. R⁶ may be substituted or unsubstituted 4 memberedheterocycloalkyl, substituted or unsubstituted 5 memberedheterocycloalkyl, substituted or unsubstituted 6 memberedheterocycloalkyl. R⁶ may be substituted or unsubstituted 5 memberedaryl, substituted or unsubstituted 6 membered aryl, substituted orunsubstituted 5 membered heteroaryl, or substituted or unsubstituted 6membered heteroaryl. R⁶ may be unsubstituted C₁-C₃ alkyl orunsubstituted 2 to 3 membered heteroalkyl. R⁶ may be unsubstituted 3membered cycloalkyl, unsubstituted 4 membered cycloalkyl, orunsubstituted 5 membered cycloalkyl. R⁶ may be unsubstituted 4 memberedheterocycloalkyl, unsubstituted 5 membered heterocycloalkyl,unsubstituted 6 membered heterocycloalkyl. R⁶ may be unsubstituted 5membered aryl, unsubstituted 6 membered aryl, unsubstituted 5 memberedheteroaryl, or unsubstituted 6 membered heteroaryl.

R⁶ may be R^(6a)-substituted or unsubstituted alkyl, R^(6a)-substitutedor unsubstituted heteroalkyl, R^(6a)-substituted or unsubstitutedcycloalkyl, R^(6a)-substituted or unsubstituted heterocycloalkyl,R^(6a)-substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R⁶ may be unsubstituted alkyl, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R⁶ may be R^(6a)-substituted or unsubstituted C₁-C₈ alkyl,R^(6a)-substituted or unsubstituted 3 to 8 membered heteroalkyl,R^(6a)-substituted or unsubstituted 3 to 8 membered cycloalkyl,R^(6a)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(6a)-substituted or unsubstituted 5 to 8 membered aryl, orR^(6a)-substituted or unsubstituted 5 to 8 membered heteroaryl. R⁶ maybe unsubstituted C₁-C₈ alkyl, unsubstituted 3 to 8 membered heteroalkyl,unsubstituted 3 to 8 membered cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, unsubstituted 5 to 8 membered aryl, or unsubstituted 5to 8 membered heteroaryl.

R⁶ may be R^(6a)-substituted or unsubstituted C₁-C₅ alkyl,R^(6a)-substituted or unsubstituted 2 to 5 membered heteroalkyl,R^(6a)-substituted or unsubstituted 3 to 5 membered cycloalkyl,R^(6a)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(6a)-substituted or unsubstituted 5 to 6 membered aryl, orR^(6a)-substituted or unsubstituted 5 to 6 membered heteroaryl. R⁶ maybe unsubstituted C₁-C₅ alkyl, unsubstituted 2 to 5 membered heteroalkyl,unsubstituted 3 to 5 membered cycloalkyl, unsubstituted 3 to 6 memberedheterocycloalkyl, unsubstituted 5 to 6 membered aryl, or orunsubstituted 5 to 6 membered heteroaryl.

R⁶ may be R^(6a)-substituted or unsubstituted C₁-C₃ alkyl orR^(6a)-substituted or unsubstituted 2 to 3 membered heteroalkyl. R⁶ maybe R^(6a)-substituted or unsubstituted 3 membered cycloalkyl,R^(6a)-substituted or unsubstituted 4 membered cycloalkyl, orR^(6a)-substituted or unsubstituted 5 membered cycloalkyl. R⁶ may beR^(6a)-substituted or unsubstituted 4 membered heterocycloalkyl,R^(6a)-substituted or unsubstituted 5 membered heterocycloalkyl, orR^(6a)-substituted or unsubstituted 6 membered heterocycloalkyl. R⁶ maybe R^(6a)-substituted or unsubstituted 5 membered aryl,R^(6a)-substituted or unsubstituted 6 membered aryl, R^(6a)-substitutedor unsubstituted 5 membered heteroaryl, or R^(6a)-substituted orunsubstituted 6 membered heteroaryl. R⁶ may be unsubstituted C₁-C₃ alkylor or unsubstituted 2 to 3 membered heteroalkyl. R⁶ may be orunsubstituted 3 membered cycloalkyl, or unsubstituted 4 memberedcycloalkyl, or or unsubstituted 5 membered cycloalkyl. R⁶ may be orunsubstituted 4 membered heterocycloalkyl, or unsubstituted 5 memberedheterocycloalkyl, or or unsubstituted 6 membered heterocycloalkyl. R⁶may be or unsubstituted 5 membered aryl, or unsubstituted 6 memberedaryl, or unsubstituted 5 membered heteroaryl, or or unsubstituted 6membered heteroaryl.

R^(6a) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, R^(6b)-substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl), R^(6b)-substituted or unsubstituted heteroalkyl (e.g. 2 to 8membered heteroalkyl), R^(6b)-substituted or unsubstituted cycloalkyl(e.g. 3 to 8 membered cycloalkyl), R^(6b)-substituted or unsubstitutedheterocycloalkyl (e.g. 3 to 6 membered heterocycloalkyl),R^(6b)-substituted or unsubstituted aryl (e.g. 5 to 6 membered aryl), orR^(6b)-substituted or unsubstituted heteroaryl (e.g. 5 to 6 memberedheteroaryl).

R^(6b) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, unsubstituted alkyl (e.g. C₁-C₈ alkyl), unsubstitutedheteroalkyl (e.g. 2 to 8 membered heteroalkyl), unsubstituted cycloalkyl(e.g. 3 to 8 membered cycloalkyl), unsubstituted heterocycloalkyl (e.g.3 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g. 5 to 6membered aryl), or unsubstituted heteroaryl (e.g. 5 to 6 memberedheteroaryl).

R⁶ may be hydrogen, halogen, R^(6a)-substituted or unsubstituted C₁-C₈alkyl, or unsubstituted 5 or 6 membered aryl. R⁶ may be hydrogen. R⁶ maybe halogen. R⁶ may be R^(6a)-substituted or unsubstituted C₁-C₈ alkyl.R⁶ may be R^(6a)-substituted or unsubstituted C₁-C₅ alkyl. R⁶ may beunsubstituted C₁-C₈ alkyl. R⁶ may be unsubstituted methyl. R⁶ may beunsubstituted ethyl. R⁶ may be unsubstituted propyl. R⁶ may beunsubstituted allyl. R⁶ may be unsubstituted aryl. R⁶ may beunsubstituted phenyl.

R⁵ and R⁶ may independently be hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, unsubstituted alkyl, orunsubstituted cycloalkyl. R⁵ and R⁶ are independently hydrogen, C₁-C₃unsubstituted alkyl or 3 to 5 membered cycloalkyl. R⁵ and R⁶ areindependently hydrogen, unsubstituted methyl, unsubstituted ethyl,unsubstituted allyl, or unsubstituted cyclopropyl. R⁵ and R⁶ mayindependently be hydrogen or halogen. R⁵ and R⁶ may independently beC₁-C₃ substituted or unsubstituted alkyl. R⁵ and R⁶ may be unsubstitutedmethyl. R⁵ and R⁶ may independently be unsubstituted methyl orunsubstituted ethyl.

R¹⁶ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂. R¹⁶ may be substituted or unsubstitutedalkyl. R¹⁶ may be substituted or unsubstituted C₁-C₈ alkyl. R¹⁶ may besubstituted or unsubstituted C₁-C₅ alkyl. R¹⁶ may be substituted orunsubstituted C₁-C₃ alkyl. R¹⁶ may be R^(16a)-substituted orunsubstituted alkyl. R¹⁶ may be R^(16a)-substituted or unsubstitutedC₁-C₈ alkyl. R¹⁶ may be R^(16a)-substituted or unsubstituted C₁-C₅alkyl. R¹⁶ may be R^(16a)-substituted or unsubstituted C₁-C₃ alkyl.

R¹⁶ may be substituted or unsubstituted heteroalkyl. R¹⁶ may besubstituted or unsubstituted 2 to 8 membered heteroalkyl. R¹⁶ may besubstituted or unsubstituted 2 to 5 membered heteroalkyl. R¹⁶ may besubstituted or unsubstituted 2 to 3 membered heteroalkyl. R¹⁶ may beR^(16a)-substituted or unsubstituted heteroalkyl. R¹⁶ may beR^(16a)-substituted or unsubstituted 2 to 8 membered heteroalkyl. R¹⁶may be R^(16a)-substituted or unsubstituted 2 to 5 membered heteroalkyl.R¹⁶ may be R^(16a)-substituted or unsubstituted 2 to 3 memberedheteroalkyl.

R¹⁶ may be substituted or unsubstituted cycloalkyl. R¹⁶ may besubstituted or unsubstituted 3 to 8 membered cycloalkyl. R¹⁶ may besubstituted or unsubstituted 3 to 5 membered cycloalkyl. R¹⁶ may besubstituted or unsubstituted 3 membered cycloalkyl. R¹⁶ may besubstituted or unsubstituted 4 membered cycloalkyl. R¹⁶ may besubstituted or unsubstituted 5 membered cycloalkyl. R¹⁶ may beR^(16a)-substituted or unsubstituted cycloalkyl. R¹⁶ may beR^(16a)-substituted or unsubstituted 3 to 8 membered cycloalkyl. R¹⁶ maybe R^(16a)-substituted or unsubstituted 3 to 5 membered cycloalkyl. R¹⁶may be R^(16a)-substituted or unsubstituted 3 membered cycloalkyl. R¹⁶may be R^(16a)-substituted or unsubstituted 4 membered cycloalkyl. R¹⁶may be R^(16a)-substituted or unsubstituted 5 membered cycloalkyl.

R¹⁶ may be substituted or unsubstituted heterocycloalkyl. R¹⁶ may besubstituted or unsubstituted 3 to 6 membered heterocycloalkyl. R¹⁶ maybe substituted or unsubstituted 4 membered heterocycloalkyl. R¹⁶ may besubstituted or unsubstituted 5 membered heterocycloalkyl. R¹⁶ may besubstituted or unsubstituted 6 membered heterocycloalkyl. R¹⁶ may beR^(16a)-substituted or unsubstituted heterocycloalkyl. R¹⁶ may beR^(16a)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl.R¹⁶ may be R^(16a)-substituted or unsubstituted 4 memberedheterocycloalkyl. R¹⁶ may be R^(16a)-substituted or unsubstituted 5membered heterocycloalkyl. R¹⁶ may be R^(16a)-substituted orunsubstituted 6 membered heterocycloalkyl.

R¹⁶ may be substituted or unsubstituted aryl. R¹⁶ may be substituted orunsubstituted 5 to 6 membered aryl. R¹⁶ may be substituted orunsubstituted 5 membered aryl. R¹⁶ may be substituted or unsubstituted 6membered aryl. R¹⁶ may be R^(16a)-substituted or unsubstituted aryl. R¹⁶may be R^(16a)-substituted or unsubstituted 5 to 6 membered aryl. R¹⁶may be R^(16a)-substituted or unsubstituted 5 membered aryl. R¹⁶ may beR^(16a)-substituted or unsubstituted 6 membered aryl. R¹⁶ may besubstituted or unsubstituted heteroaryl. R¹⁶ may be substituted orunsubstituted 5 to 6 membered heteroaryl. R¹⁶ may be substituted orunsubstituted 5 membered heteroaryl. R¹⁶ may be substituted orunsubstituted 6 membered heteroaryl. R¹⁶ may be R^(16a)-substituted orunsubstituted heteroaryl. R¹⁶ may be R^(16a)-substituted orunsubstituted 5 to 6 membered heteroaryl. R¹⁶ may be R^(16a)-substitutedor unsubstituted 5 membered heteroaryl. R¹⁶ may be R^(16a)-substitutedor unsubstituted 6 membered heteroaryl.

R^(16a) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, R^(16b)-substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl), R^(16b)-substituted or unsubstituted heteroalkyl (e.g. 2 to 8membered heteroalkyl), R^(16b)-substituted or unsubstituted cycloalkyl(e.g. 3 to 8 membered cycloalkyl), R^(16b)-substituted or unsubstitutedheterocycloalkyl (e.g. 3 to 6 membered heterocycloalkyl),R^(16b)-substituted or unsubstituted aryl (e.g. 5 to 6 membered aryl),or R^(16b)-substituted or unsubstituted heteroaryl (e.g. 5 to 6 memberedheteroaryl).

R^(16b) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, unsubstituted alkyl (e.g. C₁-C₈ alkyl), unsubstitutedheteroalkyl (e.g. 2 to 8 membered heteroalkyl), unsubstituted cycloalkyl(e.g. 3 to 8 membered cycloalkyl), unsubstituted heterocycloalkyl (e.g.3 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g. 5 to 6membered aryl), or unsubstituted heteroaryl (e.g. 5 to 6 memberedheteroaryl).

R¹⁶ may be hydrogen, halogen or substituted or unsubstituted alkyl. R¹⁶may be hydrogen. R¹⁶ may be halogen. R¹⁶ may be substituted orunsubstituted alkyl. R¹⁶ may be substituted or unsubstituted C₁-C₅alkyl. R¹⁶ may be R^(16a)-substituted or unsubstituted alkyl. R¹⁶ may beR^(16a)-substituted or unsubstituted C₁-C₅ alkyl. In embodiments, R³,R⁴, and R¹⁶ are hydrogen.

R¹⁸ may be halogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

R¹⁸ may be substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. R¹⁸ maybe unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,unsubstituted heteroaryl, or unsubstituted membered heteroaryl.

R¹⁸ may be substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted3 to 8 membered cycloalkyl, substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, substituted or unsubstituted 5 to 8 membered aryl, orsubstituted or unsubstituted 5 or 8 membered heteroaryl. R¹⁸ may beunsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 membered heteroalkyl,unsubstituted 3 to 8 membered cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, unsubstituted 5 to 8 membered aryl, or unsubstituted 5or 8 membered heteroaryl.

R¹⁸ may be substituted or unsubstituted C₁-C₅ alkyl, substituted orunsubstituted 2 to 5 membered heteroalkyl, substituted or unsubstituted3 to 5 membered cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted 5 to 6 membered aryl, orsubstituted or unsubstituted 5 or 6 membered heteroaryl. R¹⁸ may beunsubstituted C₁-C₅ alkyl, unsubstituted 2 to 5 membered heteroalkyl,unsubstituted 3 to 5 membered cycloalkyl, unsubstituted 3 to 6 memberedheterocycloalkyl, unsubstituted 5 to 6 membered aryl, or unsubstituted 5or 6 membered heteroaryl.

R¹⁸ may be substituted or unsubstituted C₁-C₃ alkyl, substituted orunsubstituted 2 to 3 membered heteroalkyl. R¹⁸ may be substituted orunsubstituted 3 membered cycloalkyl, substituted or unsubstituted 4membered cycloalkyl, or substituted or unsubstituted 5 memberedcycloalkyl. R¹⁸ may be substituted or unsubstituted 4 memberedheterocycloalkyl, substituted or unsubstituted 5 memberedheterocycloalkyl, or substituted or unsubstituted 6 memberedheterocycloalkyl. R¹⁸ may be substituted or unsubstituted 5 memberedaryl, substituted or unsubstituted 6 membered aryl, substituted orunsubstituted 6 membered heteroaryl, or substituted or unsubstituted 6membered heteroaryl. R¹⁸ may be unsubstituted C₁-C₃ alkyl orunsubstituted 2 to 3 membered heteroalkyl. R¹⁸ may be unsubstituted 3membered cycloalkyl, unsubstituted 4 membered cycloalkyl orunsubstituted 5 membered cycloalkyl. R¹⁸ may be unsubstituted 4 memberedheterocycloalkyl, unsubstituted 5 membered heterocycloalkyl, orunsubstituted 6 membered heterocycloalkyl. R¹⁸ may be unsubstituted 5membered aryl, unsubstituted 6 membered aryl, unsubstituted 5 memberedheteroaryl, or unsubstituted 6 membered heteroaryl.

R¹⁸ may be R^(18a)-substituted or unsubstituted alkyl,R^(18a)-substituted or unsubstituted heteroalkyl, R^(18a)-substituted orunsubstituted cycloalkyl, R^(18a)-substituted or unsubstitutedheterocycloalkyl, R^(18a)-substituted or unsubstituted aryl, orR^(18a)-substituted or unsubstituted heteroaryl.

R¹⁸ may be R^(18a)-substituted or unsubstituted C₁-C₈ alkyl,R^(18a)-substituted or unsubstituted 2 to 8 membered heteroalkyl,R^(18a)-substituted or unsubstituted 3 to 8 membered cycloalkyl,R^(18a)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(18a)-substituted or unsubstituted 5 to 8 membered aryl, orR^(18a)-substituted or unsubstituted 5 to 8 membered heteroaryl.

R¹⁸ may be R^(18a)-substituted or unsubstituted C₁-C₅ alkyl,R^(18a)-substituted or unsubstituted 2 to 5 membered heteroalkyl,R^(18a)-substituted or unsubstituted 3 to 5 membered cycloalkyl,R^(18a)-substituted or unsubstituted 3-6 membered heterocycloalkyl,R^(18a)-substituted or unsubstituted 5 to 6 membered aryl, orR^(18a)-substituted or unsubstituted 5 to 6 membered heteroaryl.

R¹⁸ may be R^(18a)-substituted or unsubstituted C₁-C₃ alkyl orR^(18a)-substituted or unsubstituted 2 to 3 membered heteroalkyl. R¹⁸may be R^(18a)-substituted or unsubstituted 3 membered cycloalkyl,R^(18a)-substituted or unsubstituted 4 membered cycloalkyl, orR^(18a)-substituted or unsubstituted 5 membered cycloalkyl. R¹⁸ may beR^(18a)-substituted or unsubstituted 5 membered heterocycloalkyl,R^(18a)-substituted or unsubstituted 6 membered heterocycloalkyl,R^(18a)-substituted or unsubstituted 5 membered aryl,R^(18a)-substituted or unsubstituted 6 membered aryl,R^(18a)-substituted or unsubstituted 5 membered heteroaryl, orR^(18a)-substituted or unsubstituted 6 membered heteroaryl.

R^(18a) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂Ph, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, R^(18b)-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl), R^(18b)-substituted or unsubstituted alkyl (e.g. 2 to 8membered heteroalkyl), R^(18b)-substituted or unsubstituted cycloalkyl(e.g. 3 to 8 membered cycloalkyl), R^(18b)-substituted or unsubstitutedheterocycloalkyl (e.g. 3 to 6 membered heterocycloalkyl),R^(18b)-substituted or unsubstituted aryl (e.g. 5 to 6 membered aryl),or R^(18b)-substituted or unsubstituted heteroaryl (e.g. 5 to 6 memberedheteroaryl).

R^(18b) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, unsubstituted alkyl (e.g. C₁-C₈ alkyl), unsubstitutedheterocycloalkyl (e.g. 2 to 8 membered heteroalkyl), unsubstitutedcycloalkyl (e.g. 3 to 8 membered cycloalkyl), unsubstitutedheterocycloalkyl (e.g. 3 to 6 membered heterocycloalkyl), unsubstitutedaryl (e.g. 5 to 6 membered aryl), or unsubstituted heteroaryl (e.g. 5 to6 membered heteroaryl).

R¹⁸ may be substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. R⁸ maybe R^(18a)-substituted or unsubstituted 5 membered heterocycloalkyl,R^(18a)-substituted or unsubstituted 6 membered aryl,R^(18a)-substituted or unsubstituted 6 membered heteroaryl,R^(18a)-substituted or unsubstituted 6,6 fused ringaryl-heterocycloalkyl, R^(18a)-substituted or unsubstituted 6,5 fusedring aryl-heterocycloalkyl, R^(18a)-substituted or unsubstituted 5,6fused ring aryl-heterocycloalkyl, where R^(18a) and R^(18b) are asdescribed herein, including embodiments thereof.

R¹⁸ may be R^(18a)-substituted or unsubstituted 5 memberedheterocycloalkyl, R^(5a)-substituted 6 membered aryl,R^(18a)-substituted or unsubstituted 6 membered heteroaryl,R^(18a)-substituted or unsubstituted 6,6 fused ring aryl,R^(18a)-substituted or unsubstituted 6,6 fused ring heteroaryl,R^(18a)-substituted or unsubstituted 6,5 fused ring aryl,R^(18a)-substituted or unsubstituted 6,5 fused ring heteroaryl,R^(18a)-substituted or unsubstituted 5,6 fused ring aryl,R^(18a)-substituted 5,6 fused ring heteroaryl, R^(18a)-substituted orunsubstituted 6,6 fused ring aryl-heterocycloalkyl, R^(18a)-substitutedor unsubstituted 6,5 fused ring aryl-heterocycloalkyl, orR^(18a)-substituted or unsubstituted 5,6 fused ringaryl-heterocycloalkyl.

R¹⁸ may be R^(18a)-substituted or unsubstituted 3 to 6 memberedheterocycloalkyl. The R^(18a)-substituted or unsubstituted 3 to 6membered heterocycloalkyl may be R^(18a)-substituted or unsubstitutedthiophenyl, R^(18a)-substituted or unsubstituted thiazolyl,R^(18a)-substituted or unsubstituted oxazolyl, R^(18a)-substituted orunsubstituted imidazolyl, or derivatives thereof. R⁸ may beR^(18a)-substituted or unsubstituted 6 membered aryl. R¹⁸ may beR^(18a)-substituted or unsubstituted 6 membered heteroaryl. R¹⁸ may beR^(18a)-substituted or unsubstituted 6,6 fused ringaryl-heterocycloalkyl. The R^(18a)-substituted or unsubstituted 6,6fused ring aryl-heteroaryl may be R^(18a)-substituted or unsubstituteddihydrobenzo[1,4]dioxinyl. R¹⁸ may be R^(18a)-substituted orunsubstituted 6,5 fused ring aryl-heterocycloalkyl orR^(18a)-substituted or unsubstituted 5,6 fused ringaryl-heterocycloalkyl. The R^(18a)-substituted or unsubstituted 6,5 or5,6 fused ring aryl-heterocycloalkyl may be dihydro-indenyl,benzo[1,3]dioxolyl, or indolyl. R^(18a) may be halogen, SO₂Ph, C₁-C₅R^(18b)-substituted or unsubstituted alkyl, or 2 to 5 memberedR^(18b)-substituted or unsubstituted heteroalkyl.

In one embodiment, R¹ and R¹⁸ are not joined to form a substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl (including fused cycloalkyl-aryl,heterocycloalkyl-aryl and aryl rings) or substituted or unsubstitutedheteroaryl (including fused cycloalkyl-heteroaryl,heterocycloalkyl-heteroaryl and heteroaryl rings). In one embodiment, R¹and R¹⁶ are not joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl (including fused cycloalkyl-aryl,heterocycloalkyl-aryl and aryl rings) or substituted or unsubstitutedheteroaryl (including fused cycloalkyl-heteroaryl,heterocycloalkyl-heteroaryl and heteroaryl rings).

In one embodiment, R² and R¹⁸ are not joined to form a substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl (including fused cycloalkyl-aryl,heterocycloalkyl-aryl and aryl rings) or substituted or unsubstitutedheteroaryl (including fused cycloalkyl-heteroaryl,heterocycloalkyl-heteroaryl and heteroaryl rings). In one embodiment, R²and R¹⁶ are not joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl (including fused cycloalkyl-aryl,heterocycloalkyl-aryl and aryl rings) or substituted or unsubstitutedheteroaryl (including fused cycloalkyl-heteroaryl,heterocycloalkyl-heteroaryl and heteroaryl rings).

In one embodiment, R¹ and R¹⁸ are not hydrogen. In one embodiment thecompound of formula (I) does not have the formula(3R,8S,8aR)-8-hydroxy-2-methyltetrahydro-1H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-1,4(6H)-dione.In one embodiment, the compound of formula (I) does not have the formula(3R,8S,8aR)-2-methyl-1,4-dioxohexahydro-1H-3,8a-epidithiopyrrolo[1,2-a]pyrazin-8-ylacetate. In one embodiment the compound of formula (I) does not have theformula(3R,6R,8S,8aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-8-hydroxy-2-methyltetrahydro-1H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-1,4(6H)-dione.In one embodiment, the compound does not have the formula2,3-dimethyltetrahydro-1H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-1,4(6H)-dione.In one embodiment, the compound does not have the formula3-(hydroxymethyl)-2-methyltetrahydro-1H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-1,4(6H)-dione.

The compound of formula (I) may have the formula:

p, R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁶ are as described herein.

X³ is N or CR⁷. X⁴ is N or CR⁸. X⁵ is N or CR⁹. R⁷ is hydrogen, halogen,—N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33I), —NR^(34I)R^(35I),—COOR^(33I), —CONR^(34I)R^(35I), —NO₂, —SR^(36I), —SO_(n9)R^(34I),—SO_(n9)OR^(34I), —SO_(n9)NR^(34I)R^(35I), —NHNR^(34I)R^(35I),—ONR^(34I)R^(35I), —NHC(O)NHNR^(34I)R^(35I), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R⁸ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33J), —NR^(34J)R^(35J), —COOR³³,—CONR^(34J)R^(35J), —NO₂, —SR^(36J), —SO_(n10)R^(34J),—SO_(n10)OR^(34J), —SO_(n10)NR^(34J)R^(35J), —NHNR^(34J)R^(35J),—ONR^(34J)R^(35J), —NHC(O)NHNR^(34J)R^(35J), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R⁹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33K), —NR^(34K)R^(35K), —COOR^(33K),—CONR^(34K)R^(35K), —NO₂, —SR^(36K), —SO_(n11)R^(34K),—SO_(n11)OR^(34K), —SO_(n11)NR^(34K)R^(34K)R^(35K), —NHNR^(34K)R^(35K),—ONR^(34K)R^(35K), —NHC(O)NHNR^(34K)R^(35K), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R¹⁰ and R¹¹ are independently hydrogen,halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33L),—NR^(34L)R^(35L), —COOR^(33L), —CONR^(34L)R^(35L), —NO₂, —SR^(36L),—SO_(n12)R^(34L), —SO_(n12)OR^(34L), —SO₁₂NR^(34L)R^(35L),—NHNR^(34L)R^(35L), —ONR^(34L)R^(35L), —NHC(O)NHNR^(34L)R^(35L),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or are optionally joinedtogether to form a substituted or unsubstituted cycloalkyl, asubstituted or unsubstituted heterocycloalkyl, a substituted orunsubstituted aryl, or a substituted or unsubstituted heteroaryl.R^(33I), R^(34I), R^(35I), R^(36I), R^(33J), R^(34J), R^(35J), R^(36J),R^(33K), R^(34K), R^(35K)R^(36K), R^(33L), R^(34L), R^(35L), andR^(36L), are independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. Thesymbols n9, n10, n11, and n12 are independently 1 or 2.

R¹⁰ and R¹¹ are optionally joined together to form a substituted orunsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, or a substitutedor unsubstituted heteroaryl. R⁷ and R⁸ are optionally joined together toform a substituted or unsubstituted cycloalkyl, a substituted orunsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, ora substituted or unsubstituted heteroaryl. R⁸ and R⁹ are optionallyjoined together to form a substituted or unsubstituted cycloalkyl, asubstituted or unsubstituted heterocycloalkyl, a substituted orunsubstituted aryl, or a substituted or unsubstituted heteroaryl. R⁹ andR¹⁰ are optionally joined together to form a substituted orunsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, or a substitutedor unsubstituted heteroaryl. p may be 2, 3, or 4.

When X³ is N, X⁴ may be CR⁸ and X⁵ may be CR⁹. When X⁴ is N, X³ may beCR⁷ and X⁵ may be CR⁹. When X⁵ is N, X³ may be CR⁷ and X⁴ may be CR⁸.X³, X⁴, and X⁵ may be CR⁷, CR⁸, and CR⁹ respectively.

R⁷ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl), or substituted or unsubstituted heteroalkyl (e.g. 2 to 8membered heteroalkyl). R⁷ may be halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,substituted or unsubstituted alkyl, or substituted or unsubstitutedheteroalkyl. R⁷ may be halogen, substituted or unsubstituted alkyl, orsubstituted or unsubstituted heteroalkyl. R⁷ may be halogen orsubstituted or unsubstituted alkyl. R⁷ may be halogen or unsubstitutedalkyl. R⁷ may be halogen, or unsubstituted heteroalkyl. R⁷ may behalogen, halogen, —CF₃, —CCl₃, —CBr₃, or —CI₃.

R⁷ may be substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. R⁷ maybe unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, orunsubstituted membered heteroaryl.

R⁷ may be substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted3 to 8 membered cycloalkyl, substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, substituted or unsubstituted 5 to 8 membered aryl, orsubstituted or unsubstituted 5 or 8 membered heteroaryl. R⁷ may beunsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 membered heteroalkyl,unsubstituted 3 to 8 membered cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, unsubstituted 5 to 8 membered aryl, or unsubstituted 5or 8 membered heteroaryl.

R⁷ may be substituted or unsubstituted C₁-C₅ alkyl, substituted orunsubstituted 2 to 5 membered heteroalkyl, substituted or unsubstituted3 to 5 membered cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted 5 to 6 membered aryl, orsubstituted or unsubstituted 5 to 6 membered heteroaryl. R⁷ may beunsubstituted C₁-C₅ alkyl, unsubstituted 2 to 5 membered heteroalkyl,unsubstituted 3 to 5 membered cycloalkyl, unsubstituted 3 to 6 memberedheterocycloalkyl, unsubstituted 5 to 6 membered aryl, or unsubstituted 5to 6 membered heteroaryl.

R⁷ may be substituted or unsubstituted C₁-C₃ alkyl, substituted orunsubstituted 2 to 3 membered heteroalkyl. R⁷ may be substituted orunsubstituted 3 membered cycloalkyl, substituted or unsubstituted 4membered cycloalkyl, or substituted or unsubstituted 5 memberedcycloalkyl. R⁷ may be substituted or unsubstituted 4 memberedheterocycloalkyl, substituted or unsubstituted 5 memberedheterocycloalkyl, or substituted or unsubstituted 6 memberedheterocycloalkyl. R⁷ may be substituted or unsubstituted 5 memberedaryl, substituted or unsubstituted 6 membered aryl, substituted orunsubstituted 5 membered heteroaryl, or substituted or unsubstituted 6membered heteroaryl. R⁷ may be unsubstituted C₁-C₃ alkyl orunsubstituted 2 to 3 membered heteroalkyl. R⁷ may be unsubstituted 3membered cycloalkyl, unsubstituted 4 membered cycloalkyl orunsubstituted 5 membered cycloalkyl. R⁷ may be unsubstituted 4 memberedheterocycloalkyl, unsubstituted 5 membered heterocycloalkyl, orunsubstituted 6 membered heterocycloalkyl. R⁷ may be unsubstituted 5membered aryl, unsubstituted 6 membered aryl, unsubstituted 5 memberedaryl, or unsubstituted 6 membered heteroaryl.

R⁷ may be R^(7a)-substituted or unsubstituted alkyl, R^(7a)-substitutedor unsubstituted heteroalkyl, R^(7a)-substituted or unsubstitutedcycloalkyl, R^(7a)-substituted or unsubstituted heterocycloalkyl,R^(7a)-substituted or unsubstituted aryl, or R^(7a)-substituted orunsubstituted heteroaryl.

R⁷ may be R^(7a)-substituted or unsubstituted C₁-C₈ alkyl,R^(7a)-substituted or unsubstituted 2 to 8 membered heteroalkyl,R^(7a)-substituted or unsubstituted 3 to 8 membered cycloalkyl,R^(7a)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(7a)-substituted or unsubstituted 5 to 8 membered aryl, orR^(7a)-substituted or unsubstituted 5 to 8 membered heteroaryl.

R⁷ may be R^(7a)-substituted or unsubstituted C₁-C₅ alkyl,R^(7a)-substituted or unsubstituted 2 to 5 membered heteroalkyl,R^(7a)-substituted or unsubstituted 3 to 5 membered cycloalkyl,R^(7a)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(7a)-substituted or unsubstituted 5 to 6 membered aryl, orR^(7a)-substituted or unsubstituted 5 to 6 membered heteroaryl.

R⁷ may be R^(7a)-substituted or unsubstituted C₁-C₃ alkyl orR^(7a)-substituted or unsubstituted 2 to 3 membered heteroalkyl. R⁷ maybe R^(7a)-substituted or unsubstituted 3 membered cycloalkyl,R^(7a)-substituted or unsubstituted 4 membered cycloalkyl, orR^(7a)-substituted or unsubstituted 5 membered cycloalkyl. R⁷ may beR^(7a)-substituted or unsubstituted 5 membered heterocycloalkyl,R^(7a)-substituted or unsubstituted 6 membered heterocycloalkyl,R^(7a)-substituted or unsubstituted 5 membered aryl, R^(7a)-substitutedor unsubstituted 6 membered aryl, R^(7a)-substituted or unsubstituted 5membered heteroaryl, or R^(7a)-substituted or unsubstituted 6 memberedheteroaryl.

R^(7a) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, R^(7b)-substituted or unsubstituted alky (e.g. C₁-C₈alkyl, R^(7b)-substituted or unsubstituted heteroalkyl (e.g. 2 to 8membered heteroalkyl), R^(7b)-substituted or unsubstituted cycloalkyl(e.g. 3 to 8 membered cycloalkyl), R^(7b)-substituted or unsubstitutedheterocycloalkyl (e.g. 3 to 6 membered heterocycloalkyl),R^(7b)-substituted or unsubstituted aryl (e.g. 5 to 6 membered aryl), orR^(7b)-substituted or unsubstituted heteroaryl (e.g. 5 to 6 memberedheteroaryl).

R^(7b) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, unsubstituted alky (e.g. C₁-C₈ alkyl), unsubstitutedheteroalkyl (e.g. 2 to 8 membered heteroalkyl), unsubstituted cycloalkyl(e.g. 3 to 8 membered cycloalkyl), unsubstituted heterocycloalkyl (e.g.3 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g. 5 to 6membered aryl), or unsubstituted heteroaryl (e.g. 5 to 6 memberedheteroaryl).

R⁸ and R⁹ may independently be hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂. R⁸ and R⁹ mayindependently be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, or —SO₂. R⁸ and R⁹ may independently behydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, or —NH₂.

R⁸ and R⁹ may independently be hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl), or substituted or unsubstitutedheteroalkyl (e.g. 2 to 8 membered heteroalkyl).

R⁸ and R⁹ may independently be substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. R⁸and R⁹ may independently be unsubstituted alkyl, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, unsubstituted heteroaryl, or unsubstituted memberedheteroaryl.

R⁸ and R⁹ may independently be substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted orunsubstituted 3 to 8 membered cycloalkyl, substituted or unsubstituted 3to 8 membered heterocycloalkyl, substituted or unsubstituted 5 to 8membered aryl, or substituted or unsubstituted 5 or 8 memberedheteroaryl. R⁸ and R⁹ may independently be unsubstituted C₁-C₈ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted 3 to 8 memberedcycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted 5 to 8 membered aryl, or unsubstituted 5 or 8 memberedheteroaryl.

R⁸ and R⁹ may independently be substituted or unsubstituted C₁-C₅ alkyl,substituted or unsubstituted 2 to 5 membered heteroalkyl, substituted orunsubstituted 3 to 5 membered cycloalkyl, substituted or unsubstituted 3to 6 membered heterocycloalkyl, substituted or unsubstituted 5 to 6membered aryl, or substituted or unsubstituted 5 or 6 memberedheteroaryl. R⁸ and R⁹ may independently be unsubstituted C₁-C₅ alkyl,unsubstituted 2 to 5 membered heteroalkyl, unsubstituted 3 to 5 memberedcycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl,unsubstituted 5 to 6 membered aryl, or unsubstituted 5 or 6 memberedheteroaryl.

R⁸ and R⁹ may independently be substituted or unsubstituted C₁-C₃ alkyl,substituted or unsubstituted 2 to 3 membered heteroalkyl. R⁸ and R⁹ mayindependently be substituted or unsubstituted 3 membered cycloalkyl,substituted or unsubstituted 4 membered cycloalkyl, or substituted orunsubstituted 5 membered cycloalkyl. R⁸ and R⁹ may independently besubstituted or unsubstituted 4 membered heterocycloalkyl, substituted orunsubstituted 5 membered heterocycloalkyl, or substituted orunsubstituted 6 membered heterocycloalkyl. R⁸ and R⁹ may independentlybe substituted or unsubstituted 5 membered aryl, substituted orunsubstituted 5 membered aryl, substituted or unsubstituted 6 memberedaryl, or substituted or unsubstituted 6 membered heteroaryl. R⁸ and R⁹may independently be unsubstituted C₁-C₃ alkyl or unsubstituted 2 to 3membered heteroalkyl. R⁸ and R⁹ may independently be unsubstituted 3membered cycloalkyl, unsubstituted 4 membered cycloalkyl orunsubstituted 5 membered cycloalkyl. R⁸ and R⁹ may independently beunsubstituted 4 membered heterocycloalkyl, unsubstituted 5 memberedheterocycloalkyl, or unsubstituted 6 membered heterocycloalkyl. R⁸ andR⁹ may independently be be unsubstituted 5 membered aryl, unsubstituted6 membered aryl, unsubstituted 5 membered aryl, or unsubstituted 6membered heteroaryl.

R⁸ and R⁹ may independently be R^(31a)-substituted or unsubstitutedalkyl, R^(31a)-substituted or unsubstituted heteroalkyl,R^(31a)-substituted or unsubstituted cycloalkyl, R^(31a)-substituted orunsubstituted heterocycloalkyl, R^(31a)-substituted or unsubstitutedaryl, or R^(31a)-substituted or unsubstituted heteroaryl.

R⁸ and R⁹ may independently be R^(31a)-substituted or unsubstitutedC₁-C₅ alkyl, R^(31a)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(31a)-substituted or unsubstituted 3 to 8 memberedcycloalkyl, R^(31a)-substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, R^(31a)-substituted or unsubstituted 5 to 8 memberedaryl, or R^(31a)-substituted or unsubstituted 5 to 8 memberedheteroaryl.

R⁸ and R⁹ may independently be R^(31a)-substituted or unsubstitutedC₁-C₅ alkyl, R^(31a)-substituted or unsubstituted 2 to 5 memberedheteroalkyl, R^(31a)-substituted or unsubstituted 3 to 5 memberedcycloalkyl, R^(31a)-substituted or unsubstituted 3-6 memberedheterocycloalkyl, R^(31a)-substituted or unsubstituted 5 to 6 memberedaryl, or R^(31a)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

R⁸ and R⁹ may independently be R^(31a)-substituted or unsubstitutedC₁-C₃ alkyl or R^(31a)-substituted or unsubstituted 2 to 3 memberedheteroalkyl. R⁸ and R⁹ may independently be R^(31a)-substituted orunsubstituted 3 membered cycloalkyl, R^(31a)-substituted orunsubstituted 4 membered cycloalkyl, or R^(31a)-substituted orunsubstituted 5 membered cycloalkyl. R⁸ and R⁹ may independently beR^(31a)-substituted or unsubstituted 5 membered heterocycloalkyl,R^(31a)-substituted or unsubstituted 6 membered heterocycloalkyl,R^(31a)-substituted or unsubstituted 5 membered aryl,R^(31a)-substituted or unsubstituted 6 membered aryl,R^(31a)-substituted or unsubstituted 5 membered heteroaryl, orR^(31a)-substituted or unsubstituted 6 membered heteroaryl.

R⁸ may be hydrogen, halogen or substituted or unsubstituted alkyl. R⁸may be hydrogen. R⁸ may be halogen. R⁸ may be substituted orunsubstituted alkyl. R⁸ may be substituted or unsubstituted C₁-C₅ alkyl.R⁸ may be R^(31a)-substituted alkyl. R⁸ may be hydrogen or —OR^(33J) andR⁹, R¹⁰, and R¹¹ may independently be hydrogen or halogen. R³³ may behydrogen, or unsubstituted alkyl. R⁸ may be R^(31a)-substituted C₁-C₅alkyl. R⁹ may be hydrogen, halogen substituted or unsubstituted alkyl,or unsubstituted or unsubstituted heteroalkyl. R⁹ may be substituted orunsubstituted C₁-C₅ alkyl. R⁹ may be R^(5a)-substituted or unsubstitutedalkyl. R⁹ may be R^(31a)-substituted C₁-C₅ or unsubstituted alkyl. R⁹may be R^(31a)-substituted or unsubstituted heteroalkyl. R⁹ may beR^(31a)-substituted or unsubstituted 2 to 6 membered heteroalkyl.

R^(31a) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, R^(31b)-substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl), R^(31b)-substituted or unsubstituted heteroalkyl (e.g. 2 to 8membered heteroalkyl), R^(31b)-substituted or unsubstituted cycloalkyl(e.g. 3 to 8 membered cycloalkyl), R^(31b)-substituted or unsubstitutedheterocycloalkyl (e.g. 3 to 6 membered heterocycloalkyl),R^(31b)-substituted or unsubstituted aryl (e.g. 5 to 6 membered aryl),or R^(31b)-substituted or unsubstituted heteroaryl (e.g. 5 to 6 memberedheteroaryl).

R^(31b) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, unsubstituted alky (e.g. C₁-C₈ alkyl), unsubstitutedheteroalkyl (e.g. 2 to 8 membered heteroalkyl), unsubstituted cycloalkyl(e.g. 3 to 8 membered cycloalkyl), unsubstituted heterocycloalkyl (e.g.3 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g. 5 to 6membered aryl), or unsubstituted heteroaryl (e.g. 5 to 6 memberedheteroaryl).

R⁸ and R⁹ may be joined together to form a substituted or unsubstitutedcycloalkyl (e.g. 3 to 8 membered cycloalkyl). R⁸ and R⁹ may be joinedtogether to form a substituted or unsubstituted heterocycloalkyl (e.g. 3to 8 membered heterocycloalkyl). R⁸ and R⁹ may be joined together toform a substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R⁸and R⁹ may be joined together to form a substituted or unsubstitutedheteroaryl (e.g. 3 to 8 membered heteroaryl).

R⁷ and R⁸ may be joined together to form a substituted or unsubstitutedcycloalkyl (e.g. 3 to 8 membered cycloalkyl). R⁷ and R⁸ may be joinedtogether to form a substituted or unsubstituted heterocycloalkyl (e.g. 3to 8 membered heterocycloalkyl). R⁷ and R⁸ may be joined together toform a substituted or unsubstituted aryl (e.g. 3 to 8 membered aryl). R⁷and R⁸ may be joined together to form a substituted or unsubstitutedheteroaryl (e.g. 3 to 8 membered heteroaryl).

R¹⁰ and R¹¹ may independently be hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂. R¹⁰ and R¹¹ mayindependently be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, or —SO₂. R¹⁰ and R¹¹ may independentlybe hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, or —NH₂.

R¹⁰ and R¹¹ may independently be hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl), or substituted or unsubstitutedheteroalkyl (e.g. 2 to 8 membered heteroalkyl).

R¹⁰ and R¹¹ may independently be substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. R¹⁰and R¹¹ may independently be unsubstituted alkyl, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, unsubstituted heteroaryl, or unsubstituted memberedheteroaryl.

R¹⁰ and R¹¹ may independently be substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl,substituted or unsubstituted 3 to 8 membered cycloalkyl, substituted orunsubstituted 3 to 8 membered heterocycloalkyl, substituted orunsubstituted 5 to 8 membered aryl, or substituted or unsubstituted 5 or8 membered heteroaryl. R¹⁰ and R¹¹ may independently be unsubstitutedC₁-C₈ alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted 3to 8 membered cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, unsubstituted 5 to 8 membered aryl, or unsubstituted 5or 8 membered heteroaryl.

R¹⁰ and R¹¹ may independently be substituted or unsubstituted C₁-C₅alkyl, substituted or unsubstituted 2 to 5 membered heteroalkyl,substituted or unsubstituted 3 to 5 membered cycloalkyl, substituted orunsubstituted 3-6 membered heterocycloalkyl, substituted orunsubstituted 5 to 6 membered aryl, or substituted or unsubstituted 5 or6 membered heteroaryl. R¹⁰ and R¹¹ may independently be unsubstitutedC₁-C₅ alkyl, unsubstituted 2 to 5 membered heteroalkyl, unsubstituted 3to 5 membered cycloalkyl, unsubstituted 3-6 membered heterocycloalkyl,unsubstituted 5 to 6 membered aryl, or unsubstituted 5 or 6 memberedheteroaryl.

R¹⁰ and R¹¹ may independently be substituted or unsubstituted C₁-C₃alkyl, substituted or unsubstituted 2 to 3 membered heteroalkyl. R¹⁰ andR¹¹ may independently be substituted or unsubstituted 3 memberedcycloalkyl, substituted or unsubstituted 4 membered cycloalkyl, orsubstituted or unsubstituted 5 membered cycloalkyl. R¹⁰ and R¹¹ mayindependently be substituted or unsubstituted 4 memberedheterocycloalkyl, substituted or unsubstituted 5 memberedheterocycloalkyl, or substituted or unsubstituted 6 memberedheterocycloalkyl. R¹⁰ and R¹¹ may independently be substituted orunsubstituted 5 membered aryl, substituted or unsubstituted 5 memberedaryl, substituted or unsubstituted 6 membered aryl, or substituted orunsubstituted 6 membered heteroaryl. R¹⁰ and R¹¹ may independently beunsubstituted C₁-C₃ alkyl or unsubstituted 2 to 3 membered heteroalkyl.R¹⁰ and R¹¹ may independently be unsubstituted 3 membered cycloalkyl,unsubstituted 4 membered cycloalkyl or unsubstituted 5 memberedcycloalkyl. R¹⁰ and R¹¹ may independently be unsubstituted 4 memberedheterocycloalkyl, unsubstituted 5 membered heterocycloalkyl, orunsubstituted 6 membered heterocycloalkyl. R¹⁰ and R¹¹ may independentlybe be unsubstituted 5 membered aryl, unsubstituted 5 membered aryl,unsubstituted 6 membered aryl, or unsubstituted 6 membered heteroaryl.

R¹⁰ and R¹¹ may independently be R^(32a)-substituted or unsubstitutedalkyl, R^(32a)-substituted or unsubstituted heteroalkyl,R^(32a)-substituted or unsubstituted cycloalkyl, R^(32a)-substituted orunsubstituted heterocycloalkyl, R^(32a)-substituted or unsubstitutedaryl, or R^(32a)-substituted or unsubstituted heteroaryl.

R¹⁰ and R¹¹ may independently be R^(32a)-substituted or unsubstitutedC₁-C₈ alkyl, R^(32a)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(32a)-substituted or unsubstituted 3 to 8 memberedcycloalkyl, R^(32a)-substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, R^(32a)-substituted or unsubstituted 5 to 8 memberedaryl, or R^(32a)-substituted or unsubstituted 5 to 8 memberedheteroaryl.

R¹⁰ and R¹¹ may independently be R^(32a)-substituted or unsubstitutedC₁-C₅ alkyl, R^(32a)-substituted or unsubstituted 2 to 5 memberedheteroalkyl, R^(32a)-substituted or unsubstituted 3 to 5 memberedcycloalkyl, R^(32a)-substituted or unsubstituted 3-6 memberedheterocycloalkyl, R^(32a)-substituted or unsubstituted 5 to 6 memberedaryl, or R^(32a)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

R¹⁰ and R¹¹ may independently be R^(32a)-substituted or unsubstitutedC₁-C₃ alkyl or R^(32a)-substituted or unsubstituted 2 to 3 memberedheteroalkyl. R¹⁰ and R¹¹ may independently be R^(32a)-substituted orunsubstituted 3 membered cycloalkyl, R^(32a)-substituted orunsubstituted 4 membered cycloalkyl, or R^(32a)-substituted orunsubstituted 5 membered cycloalkyl. R¹⁰ and R¹¹ may independently beR^(32a)-substituted or unsubstituted 5 membered heterocycloalkyl,R^(32a)-substituted or unsubstituted 6 membered heterocycloalkyl,R^(32a)-substituted or unsubstituted 5 membered aryl,R^(32a)-substituted or unsubstituted 6 membered aryl,R^(32a)-substituted or unsubstituted 5 membered heteroaryl, orR^(32a)-substituted or unsubstituted 6 membered heteroaryl.

R^(32a) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, R^(32b)-substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl), R^(32b)-substituted or unsubstituted heteroalkyl (e.g. 2 to 8membered heteroalkyl), R^(32b)-substituted or unsubstituted cycloalkyl(e.g. 3 to 8 membered cycloalkyl), R^(32b)-substituted or unsubstitutedheterocycloalkyl (e.g. 3 to 6 membered heterocycloalkyl),R^(32b)-substituted or unsubstituted aryl (e.g. 5 to 6 membered aryl),or R^(32b)-substituted or unsubstituted heteroaryl (e.g. 5 to 6 memberedheteroaryl).

R^(32b) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, unsubstituted alky (e.g. C₁-C₈ alkyl), unsubstitutedheteroalkyl (e.g. 2 to 8 membered heteroalkyl), unsubstituted cycloalkyl(e.g. 3 to 8 membered cycloalkyl), unsubstituted heterocycloalkyl (e.g.3 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g. 5 to 6membered aryl), or unsubstituted heteroaryl (e.g. 5 to 6 memberedheteroaryl).

R⁹ and R¹⁰ may be joined together to form a substituted or unsubstituted3 to 8 membered cycloalkyl. R⁹ and R¹⁰ may be joined together to form asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl. R⁹ andR¹⁰ may be joined together to form a substituted or unsubstituted 3 to 8membered aryl. R⁹ and R¹⁰ may be joined together to form a substitutedor unsubstituted 3 to 8 membered heteroaryl.

R¹⁰ and R¹¹ may be joined together to form a substituted orunsubstituted 3 to 8 membered cycloalkyl. R¹⁰ and R¹¹ may be joinedtogether to form a substituted or unsubstituted 3 to 8 memberedheterocycloalkyl. R¹⁰ and R¹¹ may be joined together to form asubstituted or unsubstituted 3 to 8 membered aryl. R¹⁰ and R¹¹ may bejoined together to form a substituted or unsubstituted 3 to 8 memberedheteroaryl.

In embodiments, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are independently hydrogen,halogen, C₁-C₅ unsubstituted alkyl, 2 to 5 membered unsubstitutedheteroalkyl. R⁷, R⁸, R⁹, R¹⁰ and R¹¹ may independently be hydrogen,halogen, unsubstituted methyl, —OCH₃ or —O(CH₂)₂═CH₂. R¹⁰ and R¹¹ may behydrogen.

The compound of formula (II) may have the formula:

The symbol p, X³, X⁴, X⁵, p, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰,and R¹¹ are as described herein, including embodiments thereof. R⁵ andR⁶ may independently be unsubstituted C₁-C₃ alkyl or unsubstituted 3 to5 membered cycloalkyl. R⁷, R⁸, R⁹, and R¹⁰ may independently behydrogen, halogen, unsubstituted methyl, —OCH₃ or —O(CH₂)₂═CH₂. R¹ maybe —CN or unsubstituted 2 to 5 membered heteroalkyl. R¹ may be —CN. R¹may be —COOCH₃. R¹ may be unsubstituted methyl. R² may be C₁-C₃unsubstituted alkyl. When R¹ is —CN, R² may be unsubstituted methyl. R³and R⁴ may be hydrogen. R¹⁰ and R¹¹ may be hydrogen.

The compound of formula (II) may have the formula:

In embodiments, R⁸ is hydrogen or —OR^(33J). R⁹, R¹⁰, and R¹¹ mayindependently be hydrogen or halogen. R^(33J) may be hydrogen, orunsubstituted alkyl (e.g. unsubstituted methyl, unsubstituted ethyl, orunsubstituted propyl).

The compound of formula (II) may have the formula:

R⁸ may be hydrogen or —OR^(33J). R⁹, R¹⁰, and R¹ may independently behydrogen or halogen. R^(33J) may be hydrogen, or unsubstituted alkyl.

The compound of formula (II1) may have the formula:

The compound of formula (II) may have the formula:

The compound of formula (II2) may have the formula:

The compound of formula (II) may have the formula:

The compound of formula (II3) may have the formula:

The compound of formula (II) may have the formula:

The compound of formula (I) may have the formula:

The symbol p, R¹, R², R³, R⁴, R⁵, R⁶, and R¹⁶ are as described herein,including embodiments thereof. R⁵ and R⁶ may independently beunsubstituted C₁-C₃ alkyl or unsubstituted 3 to 5 membered cycloalkyl.R⁷, R⁸, R⁹, and R¹⁰ may independently be hydrogen, halogen,unsubstituted methyl, —OCH₃ or —O(CH₂)₂═CH₂. R¹ may be —CN orunsubstituted 2 to 5 membered heteroalkyl. R¹ may be —CN. R¹ may be—COOCH₃. R¹ may be unsubstituted methyl. R² may be C₁-C₃ unsubstitutedalkyl. When R¹ is —CN, R² may be unsubstituted methyl. R³ and R⁴ may behydrogen. R¹⁰ and R¹¹ may be hydrogen.

X⁶ is CR²¹ or N. X⁷ is CR²²R²³, S, O, or NR²³. R¹⁹, R²⁰, R²¹, R²² andR²³ are independently hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(33M), —NR^(34M)R^(35M), —COOR^(33M), —CONR^(34M)R^(35M),—NO₂, —SR^(36M), —SO_(n13)R^(34M), —SO_(n13)OR^(34M),—SO_(n13)NR^(34M)R^(35M), —NHNR^(34M)R^(35M), —ONR^(34M)R^(35M),—NHC(O)NHNR^(34M)R^(35M), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.R^(33M), R^(34M), R^(35M), and R^(36M) are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. The symbol n13 is 1 or 2.

R¹⁹, R²⁰, R²¹, R²² and R²³ may independently be hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂. R¹⁹,R²⁰, R²¹, R²² and R²³ may independently be substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl,substituted or unsubstituted 3 to 6 membered cycloalkyl, substituted orunsubstituted 3 to 6 membered heterocycloalkyl, substituted orunsubstituted 5 to 6 membered aryl, substituted or unsubstituted 5 to 6membered heteroaryl. R¹⁹, R²⁰, R²¹, R²² and R²³ may be fused to form asubstituted or unsubstituted 5 or 6 membered heterocycloalkyl, asubstituted or unsubstituted 5 or 6 membered aryl, or a substituted orunsubstituted 5 or 6 membered heteroaryl.

R¹⁹, R²⁰, R²¹, R²² and R²³ may independently be substituted orunsubstituted alkyl. R¹⁹, R²⁰, R²¹, R²² and R²³ may independently besubstituted or unsubstituted C₁-C₈ alkyl. R¹⁹, R²⁰, R²¹, R²² and R²³ mayindependently be substituted or unsubstituted C₁-C₅ alkyl. R¹⁹, R²⁰,R²¹, R²² and R²³ may independently be substituted or unsubstituted C₁-C₃alkyl. R¹⁹, R²⁰, R²¹, R²² and R²³ may independently beR^(37a)-substituted or unsubstituted alkyl. R¹⁹, R²⁰, R²¹, R²² and R²³may independently be R^(37a)-substituted or unsubstituted C₁-C₈ alkyl.R¹⁹, R²⁰, R²¹, R²² and R²³ may independently be R^(37a)-substituted orunsubstituted C₁-C₅ alkyl. R¹⁹, R²⁰, R²¹, R²² and R²³ may independentlybe R^(37a)-substituted or unsubstituted C₁-C₃ alkyl.

R¹⁹, R²⁰, R²¹, R²² and R²³ may independently be substituted orunsubstituted heteroalkyl. R¹⁹, R²⁰, R²¹, R²² and R²³ may independentlybe substituted or unsubstituted 2 to 8 membered heteroalkyl. R¹⁹, R²⁰,R²¹, R²² and R²³ may independently be substituted or unsubstituted 2 to5 membered heteroalkyl. R¹⁹, R²⁰, R²¹, R²² and R²³ may independently besubstituted or unsubstituted 2 to 3 membered heteroalkyl. R¹⁹, R²⁰, R²¹,R²² and R²³ may independently be R^(37a)-substituted or unsubstitutedheteroalkyl. R¹⁹, R²⁰, R²¹, R²² and R²³ may independently beR^(37a)-substituted or unsubstituted 2 to 8 membered heteroalkyl. R¹⁹,R²⁰, R²¹, R²² and R²³ may independently be R^(37a)-substituted orunsubstituted 2 to 5 membered heteroalkyl. R¹⁹, R²⁰, R²¹, R²² and R²³may independently be R^(37a)-substituted or unsubstituted 2 to 3membered heteroalkyl.

R¹⁹, R²⁰, R²¹, R²² and R²³ may independently be substituted orunsubstituted cycloalkyl. R¹⁹, R²⁰, R²¹, R²² and R²³ may independentlybe substituted or unsubstituted 3 to 8 membered cycloalkyl. R¹⁹, R²⁰,R²¹, R²² and R²³ may independently be substituted or unsubstituted 3 to5 membered cycloalkyl. R¹⁹, R²⁰, R²¹, R²² and R²³ may independently besubstituted or unsubstituted 3 membered cycloalkyl. R¹⁹, R²⁰, R²¹, R²²and R²³ may independently be substituted or unsubstituted 4 memberedcycloalkyl. R¹⁹, R²⁰, R²¹, R²² and R²³ may independently be substitutedor unsubstituted 5 membered cycloalkyl. R¹⁹, R²⁰, R²¹, R²² and R²³ mayindependently be R^(37a)-substituted or unsubstituted cycloalkyl. R¹⁹,R²⁰, R²¹, R²² and R²³ may independently be R^(37a)-substituted orunsubstituted 3 to 8 membered cycloalkyl. R¹⁹, R²⁰, R²¹, R²² and R²³ mayindependently be R^(37a)-substituted or unsubstituted 3 to 5 memberedcycloalkyl. R¹⁹, R²⁰, R²¹, R²² and R²³ may independently beR^(37a)-substituted or unsubstituted 3 membered cycloalkyl. R¹⁹, R²⁰,R²¹, R²² and R²³ may independently be R^(37a)-substituted orunsubstituted 4 membered cycloalkyl. R¹⁹, R²⁰, R²¹, R²² and R²³ mayindependently be R^(37a)-substituted or unsubstituted 5 memberedcycloalkyl.

R¹⁹, R²⁰, R²¹, R²² and R²³ may independently be substituted orunsubstituted heterocycloalkyl. R¹⁹, R²⁰, R²¹, R²² and R²³ mayindependently be substituted or unsubstituted 3 to 6 memberedheterocycloalkyl. R¹⁹, R²⁰, R²¹, R²² and R²³ may independently besubstituted or unsubstituted 4 membered heterocycloalkyl. R¹⁹, R²⁰, R²¹,R²² and R²³ may independently be substituted or unsubstituted 5 memberedheterocycloalkyl. R¹⁹, R²⁰, R²¹, R²² and R²³ may independently besubstituted or unsubstituted 6 membered heterocycloalkyl. R¹⁹, R²⁰, R²¹,R²² and R²³ may independently be R^(37a)-substituted or unsubstitutedheterocycloalkyl. R¹⁹, R²⁰, R²¹, R²² and R²³ may independently beR^(37a)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl.R¹⁹, R²⁰, R²¹, R²² and R²³ may independently be R^(37a)-substituted orunsubstituted 4 membered heterocycloalkyl. R¹⁹, R²⁰, R²¹, R²² and R²³may independently be R^(37a)-substituted or unsubstituted 5 memberedheterocycloalkyl. R¹⁹, R²⁰, R²¹, R²² and R²³ may independently beR^(37a)-substituted or unsubstituted 6 membered heterocycloalkyl.

R¹⁹, R²⁰, R²¹, R²² and R²³ may independently be substituted orunsubstituted aryl. R¹⁹, R²⁰, R²¹, R²² and R²³ may independently besubstituted or unsubstituted 5 to 6 membered aryl. R¹⁹, R²⁰, R²¹, R²²and R²³ may independently be substituted or unsubstituted 5 memberedaryl. R¹⁹, R²⁰, R²¹, R²² and R²³ may independently be substituted orunsubstituted 6 membered aryl. R¹⁹, R²⁰, R²¹, R²² and R²³ mayindependently be R^(37a)-substituted or unsubstituted aryl. R¹⁹, R²⁰,R²¹, R²² and R²³ may independently be R^(37a)-substituted orunsubstituted 5 to 6 membered aryl. R¹⁹, R²⁰, R²¹, R²² and R²³ mayindependently be R^(37a)-substituted or unsubstituted 5 membered aryl.R¹⁹, R²⁰, R²¹, R²² and R²³ may independently be R^(37a)-substituted orunsubstituted 6 membered aryl. R¹⁹, R²⁰, R²¹, R²² and R²³ mayindependently be substituted or unsubstituted heteroaryl. R¹⁹, R²⁰, R²¹,R²² and R²³ may independently be substituted or unsubstituted 5 to 6membered heteroaryl. R¹⁹, R²⁰, R²¹, R²² and R²³ may independently besubstituted or unsubstituted 5 membered heteroaryl. R¹⁹, R²⁰, R²¹, R²²and R²³ may independently be substituted or unsubstituted 6 memberedheteroaryl. R¹⁹, R²⁰, R²¹, R²² and R²³ may independently beR^(37a)-substituted or unsubstituted heteroaryl. R¹⁹, R²⁰, R²¹, R²² andR²³ may independently be R^(37a)-substituted or unsubstituted 5 to 6membered heteroaryl. R¹⁹, R²⁰, R²¹, R²² and R²³ may independently beR^(37a)-substituted or unsubstituted 5 membered heteroaryl. R¹⁹, R²⁰,R²¹, R²² and R²³ may independently be R^(37a)-substituted orunsubstituted 6 membered heteroaryl. R^(37a) is as described herein,including embodiments thereof.

R¹⁹ and R²⁰ may optionally be bonded together to form a substituted orunsubstituted 3 to 6 membered cycloalkyl, substituted or unsubstituted 3to 6 membered heterocycloalkyl, substituted or unsubstituted 5 to 6membered aryl, or substituted or unsubstituted 5 to 6 memberedheteroaryl.

R¹⁹ and R²² may optionally be bonded together to form a substituted orunsubstituted 3 to 6 membered cycloalkyl, substituted or unsubstituted 3to 6 membered heterocycloalkyl, substituted or unsubstituted 5 to 6membered aryl, or substituted or unsubstituted 5 to 6 memberedheteroaryl.

R²⁰ and R²¹ may optionally be bonded together to form a substituted orunsubstituted 3 to 6 membered cycloalkyl, substituted or unsubstituted 3to 6 membered heterocycloalkyl, substituted or unsubstituted 5 to 6membered aryl, or substituted or unsubstituted 5 to 6 memberedheteroaryl.

When X⁷ is S, X⁶ may be N or CR²¹. When X⁷ is NH, X⁶ may be N or CR²¹.When X⁷ is NR²³, X⁶ may CR²¹ or N. When X⁷ is O, X⁶ may be N, CH, orCR²¹. In certain embodiments, X⁷ is S and X⁶ is CH. p may be 2, 3, or 4.In certain embodiments p is 2.

The compound of formula (III) may have the formula:

The compound of formula (III) may have the formula:

The compound of formula (III1) may have the formula:

The compound of formula (III) may have the formula:

The compound of formula (I) may have the formula:

The symbol p, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, and R¹⁶ are asdescribed herein, including embodiments thereof. R¹², R¹³, R¹⁴, R¹⁵,R²¹, R^(21A), R²², and R^(22A) are independently hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33M), —NR^(34M)R^(35M),—COOR^(33M), —CONR^(34M)R^(35M), —NO₂, —SR^(36M), —SO_(n13)R^(34M),—SO_(n13)OR^(34M), —SO_(n13)NR^(34M)R^(35M), —NHNR^(34M)R^(35M),—ONR^(34M)R^(35M), —NHC(O)NHNR^(34M)R^(35M), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R^(33M)R^(34M), R^(35M), and R^(36M) areindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. Thesymbol n13 is 1 or 2.

X¹ is CR²¹R^(21A), O, NR^(21A), or S. X² is CR²²R^(22A), O, NR^(22A), orS. R⁵ and R⁶ may independently be unsubstituted C₁-C₃ alkyl orunsubstituted 3 to 5 membered cycloalkyl. R⁷, R⁸, R⁹, and R¹⁰ mayindependently be hydrogen, halogen, unsubstituted methyl, —OCH₃ or—O(CH₂)₂═CH₂. R¹ may be —CN or unsubstituted 2 to 5 memberedheteroalkyl. R¹ may be —CN. R¹ may be —COOCH₃. R¹ may be unsubstitutedmethyl. R² may be C₁-C₃ unsubstituted alkyl. When R¹ is —CN, R² may beunsubstituted methyl. R³ and R⁴ may be hydrogen. R¹⁰ and R¹¹ may behydrogen. R¹², R¹³, R¹⁴, and R¹⁵ may be hydrogen.

R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A) may independently behydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A) mayindependently be substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted 2 to 8 membered heteroalkyl, substituted orunsubstituted 3 to 6 membered cycloalkyl, substituted or unsubstituted 3to 6 membered heterocycloalkyl, substituted or unsubstituted 5 to 6membered aryl, substituted or unsubstituted 5 to 6 membered heteroaryl.R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A) may be fused to form asubstituted or unsubstituted 5 or 6 membered heterocycloalkyl, asubstituted or unsubstituted 5 or 6 membered aryl, or a substituted orunsubstituted 5 or 6 membered heteroaryl.

R¹², R¹³, R¹⁴, and R¹⁵ may independently be substituted or unsubstitutedalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A) mayindependently be substituted or unsubstituted C₁—C alkyl. R¹², R¹³, R¹⁴,R¹⁵ R²¹, R^(21A), R²², and R^(22A) may independently be substituted orunsubstituted C₁-C₅ alkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², andR^(22A) may independently be substituted or unsubstituted C₁-C₃ alkyl.R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A) may independently beR^(37a)-substituted or unsubstituted alkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹,R^(21A), R²², and R^(22A) may independently be R^(37a)-substituted orunsubstituted C₁-C₈ alkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², andR^(22A) may independently be R^(37a)-substituted or unsubstituted C₁-C₅alkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A) mayindependently be R^(37a)-substituted or unsubstituted C₁-C₃ alkyl.

R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A) may independently besubstituted or unsubstituted heteroalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹,R^(21A), R²², and R^(22A) may independently be substituted orunsubstituted 2 to 8 membered heteroalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹,R^(21A), R²², and R^(22A) may independently be substituted orunsubstituted 2 to 5 membered heteroalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹,R^(21A), R²², and R^(22A) may independently be substituted orunsubstituted 2 to 3 membered heteroalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹,R^(21A), R²², and R^(22A) may independently be R^(37a)-substituted orunsubstituted heteroalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², andR^(22A) may independently be R^(37a)-substituted or unsubstituted 2 to 8membered heteroalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A)may independently be R^(37a)-substituted or unsubstituted 2 to 5membered heteroalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A)may independently be R^(37a)-substituted or unsubstituted 2 to 3membered heteroalkyl.

R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A) may independently besubstituted or unsubstituted cycloalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹,R^(21A), R²², and R^(22A) may independently be substituted orunsubstituted 3 to 8 membered cycloalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹,R^(21A), R²², and R^(22A) may independently be substituted orunsubstituted 3 to 5 membered cycloalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹,R^(21A), R²², and R^(22A) may independently be substituted orunsubstituted 3 membered cycloalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A),R²², and R^(22A) may independently be substituted or unsubstituted 4membered cycloalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A)may independently be substituted or unsubstituted 5 membered cycloalkyl.R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A) may independently beR^(37a)-substituted or unsubstituted cycloalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹,R^(21A), R²², and R^(22A) may independently be R^(37a)-substituted orunsubstituted 3 to 8 membered cycloalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹,R^(21A), R²², and R^(22A) may independently be R^(37a)-substituted orunsubstituted 3 to 5 membered cycloalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹,R^(21A), R²², and R^(22A) may independently be R^(37a)-substituted orunsubstituted 3 membered cycloalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A),R²², and R^(22A) may independently be R^(37a)-substituted orunsubstituted 4 membered cycloalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A),R²², and R^(22A) may independently be R^(37a)-substituted orunsubstituted 5 membered cycloalkyl.

R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A) may independently besubstituted or unsubstituted heterocycloalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹,R^(21A), R²², and R^(22A) may independently be substituted orunsubstituted 3 to 6 membered heterocycloalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹,R^(21A), R²², and R^(22A) may independently be substituted orunsubstituted 4 membered heterocycloalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹,R^(21A), R²², and R^(22A) may independently be substituted orunsubstituted 5 membered heterocycloalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹,R^(21A), R²², and R^(22A) may independently be substituted orunsubstituted 6 membered heterocycloalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹,R^(21A), R²², and R^(22A) may independently be R^(37a)-substituted orunsubstituted heterocycloalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²²,and R^(22A) may independently be R^(37a)-substituted or unsubstituted 3to 6 membered heterocycloalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²²,and R^(22A) may independently be R^(37a)-substituted or unsubstituted 4membered heterocycloalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², andR^(22A) may independently be R^(37a)-substituted or unsubstituted 5membered heterocycloalkyl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², andR^(22A) may independently be R^(37a)-substituted or unsubstituted 6membered heterocycloalkyl.

R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A) may independently besubstituted or unsubstituted aryl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²²,and R^(22A) may independently be substituted or unsubstituted 5 to 6membered aryl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A) mayindependently be substituted or unsubstituted 5 membered aryl. R¹², R¹³,R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A) may independently be substitutedor unsubstituted 6 membered aryl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²²and R^(22A) may independently be R^(37a)-substituted or unsubstitutedaryl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A)R²², and R^(22A) may independentlybe R^(37a)-substituted or unsubstituted 5 to 6 membered aryl. R¹², R¹³,R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A) may independently beR^(37a)-substituted or unsubstituted 5 membered aryl. R¹², R¹³, R¹⁴, R¹⁵R²¹, R^(21A), R²², and R^(22A) may independently be R^(37a)-substitutedor unsubstituted 6 membered aryl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²²,and R^(22A) may independently be substituted or unsubstitutedheteroaryl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A) mayindependently be substituted or unsubstituted 5 to 6 memberedheteroaryl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A) mayindependently be substituted or unsubstituted 5 membered heteroaryl.R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A) may independently besubstituted or unsubstituted 6 membered heteroaryl. R¹², R¹³, R¹⁴, R¹⁵R²¹, R^(21A), R²², and R^(22A) may independently be R^(37a)-substitutedor unsubstituted heteroaryl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², andR^(22A) may independently be R^(37a)-substituted or unsubstituted 5 to 6membered heteroaryl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A)may independently be R^(37a)-substituted or unsubstituted 5 memberedheteroaryl. R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A) mayindependently be R^(37a)-substituted or unsubstituted 6 memberedheteroaryl.

The compound of formula (IV) may have the formula:

The compound of formula (IV) may have the formula:

The compound of formula (IV1) may have the formula:

The compound of formula (IV1) may have the formula:

The compound of formula (IV2) may have the formula:

The compound of formula (IV2) may have the formula:

The compound of formula (I) may have the formula:

X¹, X², p, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹ R¹², R¹³, and R¹⁶ are asdescribed herein, including embodiments thereof.

In embodiments R⁷ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(33I), —NR^(34I)R^(35I), —COOR^(33I), —CONR^(34I)R^(35I),—NO₂, —SR^(36I), —SO_(n9)R³⁴, —SO_(n9)OR^(34I), —SO_(n9)NR^(34I)R^(35I),—NHNR^(34I)R^(35I), —ONR³⁴R³⁵, —NHC(O)NHNR^(34I)R^(35I), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In embodiments R¹⁰ and R¹¹ are independentlyhydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33L),—NR^(34L)R^(35L), —COOR^(33L), —CONR^(34L)R^(35L), —NO₂, —SR^(36L),—SO_(n12)R^(34L), —SO_(n12)OR^(34L), —SO_(n12)NR^(34L)R^(35L),—NHNR^(34L)R^(35L), —ONR^(34L)R^(35L), —NHC(O)NHNR^(34L)R^(35L),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or are optionally joinedtogether to form a substituted or unsubstituted cycloalkyl, asubstituted or unsubstituted heterocycloalkyl, a substituted orunsubstituted aryl, or a substituted or unsubstituted heteroaryl. Inembodiments, R¹², R¹³, R²¹, R^(21A), R²² and R^(22A) are independentlyhydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33M),—NR^(34M)R^(35M), —COOR^(33M), —CONR^(34M)R^(35M), —NO₂, —SR^(36M),—SO_(n13)R^(34M), —SO_(n13)OR^(34M), —SO_(n13)NR^(34M)R^(35M),—NHNR^(34M)R^(35M), —ONR^(34M)R^(35M), —NHC(O)NHNR^(34M)R^(35M),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R^(33M), R^(34M), R^(35M), andR^(36M) are independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. Thesymbols n9, n11, and n13 may independently be 1 or 2.

R⁵ and R⁶ may independently be unsubstituted C₁-C₃ alkyl orunsubstituted 3 to 5 membered cycloalkyl. R⁷, R¹⁰, and R¹¹ mayindependently be hydrogen, halogen, unsubstituted methyl, —OCH₃ or—O(CH₂)₂═CH₂. R¹ may be —CN or unsubstituted 2 to 5 memberedheteroalkyl. R¹ may be —CN. R¹ may be —COOCH₃. R¹ may be unsubstitutedmethyl. R² may be C₁-C₃ unsubstituted alkyl. When R¹ is —CN, R² may beunsubstituted methyl. R³ and R⁴ may be hydrogen. R¹⁰ and R¹¹ may behydrogen. R¹² and R¹³ may be hydrogen.

The compound of formula (V) may have the formula:

The compound of formula (V) may have the formula:

The compound of formula (V1) may have the formula:

The compound of formula (V1) may have the formula:

The compound of formula (V2) may have the formula:

The compound of formula (V) may have the formula:

The compound of formula (V2) may have the formula:

The compound of formula (V) may have the formula:

The compound of formula (V1) may have the formula:

The compound of formula (V3) may have the formula:

The compound of formula (V4) may have the formula:

The compound of formula (I) may have the formula:

X¹, X², p, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹¹, R¹², R¹³, and R¹⁶ are asdescribed herein, including embodiments thereof. R¹⁷ is hydrogen,halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33P),—NR^(34P)R^(35P), —COOR³³, —CONR^(34P)R^(35P), —NO₂, —SR^(36P),—SO_(n15)R³⁴, —SO_(n15)OR³⁴, —SO_(n15)NR^(34P)R³⁵, —NHNR^(34P)R^(35P),—ONR³⁴R³⁵, —NHC(O)NHNR^(34P)R^(35P), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl, orare optionally bonded together to form a substituted or unsubstitutedcycloalkyl, a substituted or unsubstituted heterocycloalkyl, asubstituted or unsubstituted aryl, or a substituted or unsubstitutedheteroaryl. R^(33I), R^(34I), R^(35I), R^(36I), R^(33L), R^(34L),R^(35L), R^(36L), R^(33M), R^(34M), R^(35M), R^(36M), R^(33P), R^(34P),R^(35P), and R^(36P) are independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. The symbols n9, n12, n13 and n15 areindependently 1 or 2.

In embodiments X¹ is CR²¹R^(21A), O, NR^(21A), or S. In embodiments X²is CR²²R^(22A), O, NR^(22A), or S. In embodiments R⁷ is hydrogen,halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33I),—NR^(34I)R^(35I), —COOR^(33I), —CONR^(34I)R^(35I), —NO₂, —SR^(36I),—SO_(n9)R^(34I), —SO_(n9)OR^(34I), —SO_(n9)NR^(34I)R^(35I),—NHNR^(34I)R^(35I), —NR^(34I)R^(35I), —NHC(O)NHNR^(34I)R^(35I),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In embodiments R¹¹ is hydrogen,halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33L),—NR^(34L)R^(35L), —COOR^(33L), —CONR^(34L)R^(35L), —NO₂, —SR^(36L),—SO_(n12)R^(34L), —SO_(n12)OR^(34L), —SO_(n12)NR^(34L)R^(35L),—NHNR^(34L)R^(35L), —ONR^(34L)R^(35L), —NHC(O)NHNR^(34L)R^(35L),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or are optionally joinedtogether to form a substituted or unsubstituted cycloalkyl, asubstituted or unsubstituted heterocycloalkyl, a substituted orunsubstituted aryl, or a substituted or unsubstituted heteroaryl. Inembodiments, R¹², R¹³, R²¹, R^(21A), R²², and R^(22A) are independentlyhydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33M),—NR^(34M)R^(35M), —COOR^(33M), —CONR^(34M)R^(35M), —NO₂, —SR^(36M),—SO_(n13)R^(34M), —SO_(n13)OR^(34M), —SO_(n13)NR^(34M)R^(35M),—NHNR^(34M)R^(35M), —ONR^(34M)R^(35M), —NHC(O)NHNR^(34M)R^(35M),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

R⁵ and R⁶ may independently be unsubstituted C₁-C₃ alkyl orunsubstituted 3 to 5 membered cycloalkyl. R⁷, R¹⁰, and R¹¹ mayindependently be hydrogen, halogen, unsubstituted methyl, —OCH₃ or—O(CH₂)₂═CH₂. R¹ may be —CN or unsubstituted 2 to 5 memberedheteroalkyl. R¹ may be —CN. R¹ may be —COOCH₃. R¹ may be unsubstitutedmethyl. R² may be C₁-C₃ unsubstituted alkyl. When R¹ is —CN, R² may beunsubstituted methyl. R³ and R⁴ may be hydrogen. R¹⁰ and R¹¹ may behydrogen. R¹² and R¹³ may be hydrogen. R⁷, R¹⁰, and R¹⁷ may be hydrogen.

R¹⁷ may be hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂. R¹⁷ may be substituted or unsubstitutedalkyl. R¹⁷ may be substituted or unsubstituted C₁-C₈ alkyl. R¹⁷ may besubstituted or unsubstituted C₁-C₅ alkyl. R¹⁷ may be substituted orunsubstituted C₁-C₃ alkyl. R¹ may be R^(17a)-substituted orunsubstituted alkyl. R¹⁷ may be R^(17a)-substituted or unsubstitutedC₁-C₈ alkyl. R¹ may be R^(17a)-substituted or unsubstituted C₁-C₅ alkyl.R¹⁷ may be R^(17a)-substituted or unsubstituted C₁-C₃ alkyl.

R¹⁷ may be substituted or unsubstituted heteroalkyl. R¹⁷ may besubstituted or unsubstituted 2 to 8 membered heteroalkyl. R¹⁷ may besubstituted or unsubstituted 2 to 5 membered heteroalkyl. R¹⁷ may besubstituted or unsubstituted 2 to 3 membered heteroalkyl. R¹⁷ may beR^(17a)-substituted or unsubstituted heteroalkyl. R¹⁷ may beR^(17a)-substituted or unsubstituted 2 to 8 membered heteroalkyl. R¹⁷may be R^(17a)-substituted or unsubstituted 2 to 5 membered heteroalkyl.R¹⁷ may be R^(17a)-substituted or unsubstituted 2 to 3 memberedheteroalkyl.

R¹⁷ may be substituted or unsubstituted cycloalkyl. R¹⁷ may besubstituted or unsubstituted 3 to 8 membered cycloalkyl. R¹⁷ may besubstituted or unsubstituted 3 to 5 membered cycloalkyl. R¹⁷ may besubstituted or unsubstituted 3 membered cycloalkyl. R¹⁷ may besubstituted or unsubstituted 4 membered cycloalkyl. R¹⁷ may besubstituted or unsubstituted 5 membered cycloalkyl. R¹⁷ may beR^(17a)-substituted or unsubstituted cycloalkyl. R¹⁷ may beR^(17a)-substituted or unsubstituted 3 to 8 membered cycloalkyl. R¹⁷ maybe R^(17a)-substituted or unsubstituted 3 to 5 membered cycloalkyl. R¹⁷may be R^(17a)-substituted or unsubstituted 3 membered cycloalkyl. R¹⁷may be R^(17a)-substituted or unsubstituted 4 membered cycloalkyl. R¹⁷may be R^(17a)-substituted or unsubstituted 5 membered cycloalkyl.

R¹⁷ may be substituted or unsubstituted heterocycloalkyl. R¹⁷ may besubstituted or unsubstituted 3 to 6 membered heterocycloalkyl. R¹⁷ maybe substituted or unsubstituted 4 membered heterocycloalkyl. R¹⁷ may besubstituted or unsubstituted 5 membered heterocycloalkyl. R¹⁷ may besubstituted or unsubstituted 6 membered heterocycloalkyl. R¹⁷ may beR^(17a)-substituted or unsubstituted heterocycloalkyl. R¹⁷ may beR^(17a)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl.R¹⁷ may be R^(17a)-substituted or unsubstituted 4 memberedheterocycloalkyl. R¹⁷ may be R^(17a)-substituted or unsubstituted 5membered heterocycloalkyl. R¹⁷ may be R^(17a)-substituted orunsubstituted 6 membered heterocycloalkyl.

R¹⁷ may be substituted or unsubstituted aryl. R¹⁷ may be substituted orunsubstituted 5 to 6 membered aryl. R¹⁷ may be substituted orunsubstituted 5 membered aryl. R¹⁷ may be substituted or unsubstituted 6membered aryl. R¹⁷ may be R^(17a)-substituted or unsubstituted aryl. R¹⁷may be R^(17a)-substituted or unsubstituted 5 to 6 membered aryl. R¹⁷may be R^(17a)-substituted or unsubstituted 5 membered aryl. R¹⁷ may beR^(17a)-substituted or unsubstituted 6 membered aryl. R¹⁷ may besubstituted or unsubstituted heteroaryl. R¹⁷ may be substituted orunsubstituted 5 to 6 membered heteroaryl. R¹⁷ may be substituted orunsubstituted 5 membered heteroaryl. R¹⁷ may be substituted orunsubstituted 6 membered heteroaryl. R¹⁷ may be R^(17a)-substituted orunsubstituted heteroaryl. R¹⁷ may be R^(17a)-substituted orunsubstituted 5 to 6 membered heteroaryl. R¹⁷ may be R^(17a)-substitutedor unsubstituted 5 membered heteroaryl. R¹⁷ may be R^(17a)-substitutedor unsubstituted 6 membered heteroaryl.

R^(17a) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, R^(17b)-substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl), R^(17b)-substituted or unsubstituted heteroalkyl (e.g. 2 to 8membered heteroalkyl), R^(17b)-substituted or unsubstituted cycloalkyl(e.g. C₃-C₈ cycloalkyl), R^(17b)-substituted or unsubstitutedheterocycloalkyl (e.g. 3 to 6 membered heterocycloalkyl),R^(17b)-substituted or unsubstituted aryl (e.g. 5 or 6 membered aryl),or R^(17b)-substituted or unsubstituted heteroaryl (e.g. 5 or 6 memberedheteroaryl).

R^(17b) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, unsubstituted alkyl (e.g. C₁-C₈ alkyl), unsubstitutedheteroalkyl (e.g. 2 to 8 membered heteroalkyl), unsubstituted cycloalkyl(e.g. C₃-C₈ cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 6membered heterocycloalkyl), unsubstituted aryl (e.g. 5 or 6 memberedaryl), or unsubstituted heteroaryl (e.g. 5 or 6 membered heteroaryl).

The compound of formula (VI) may have the formula:

The compound formula (VI) may have the formula:

The compound of formula (VI1) may have the formula:

The compound of formula (VI) may have the formula:

In another aspect is a compound having the formula:

R¹, R², R³, R⁴, R⁵, R⁶, R¹⁶ and R¹⁸ are as described herein, includingembodiments thereof. R²⁵ and R²⁶ are independently hydrogen substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In embodiments, R²⁵ and R²⁶ are independently, hydrogen, trityl,para-methoxybenzyl, para-methylbenzyl, acetamidomethyl, tert-butyl,tert-butyl thiol, unsubstituted benzyl, unsubstituted methyl,phenylacyl, or unsubstituted benzyloxycarbonyl.

The compound of formula (VII) may have the formula:

X³, X⁴, X⁵ and R¹, R², R³, R⁴, R⁵, R⁶, R¹⁰, R¹¹, R¹⁶, R²⁵, and R²⁶ areas described herein, including embodiments thereof. R⁸ and R⁹ may bebound together to form an unsubstituted or R^(31a)-substituted 5 or 6membered heterocycloalkyl. R⁸ and R⁹ may be oxo. R⁵ and R⁶ mayindependently be hydrogen, unsubstituted 3 to 5 membered cycloalkyl, orR^(5a)-substituted or unsubstituted C₁-C₅ alkyl. R^(5a) may beunsubstituted 2 to 5 membered heteroalkyl or 5 to 6 memberedheterocycloalkyl. R^(5a) may be —N(CH₃)₂ or unsubstituted morpholino. R¹may be —CN. R¹ may be —COOCH₃. R¹ may be unsubstituted methyl. R² may beC₁-C₃ unsubstituted alkyl. When R¹ is —CN, R² may be unsubstitutedmethyl. R¹¹ may be hydrogen or halogen.

The compound of formula (VIII) may have the formula:

The compound of formula (VII) may have the formula:

X⁶, X⁷, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁹, R²⁰, R²⁵, and R²⁶ are asdescribed herein, including embodiments thereof. R⁵ and R⁶ mayindependently be unsubstituted 3 to 5 membered cycloalkyl orR^(5a)-substituted or unsubstituted C₁-C₅ alkyl. R^(5a) may beunsubstituted 2 to 5 membered heteroalkyl or 5 to 6 memberedheterocycloalkyl. R^(5a) may be —N(CH₃)₂ or unsubstituted morpholino. R¹may be —CN. R¹ may be —COOCH₃. R¹ may be unsubstituted methyl. R² may beC₁-C₃ unsubstituted alkyl. When R¹ is —CN, R² may be unsubstitutedmethyl. R¹¹ may be hydrogen or halogen.

The compound of formula (IX) may have the formula:

The compound of formula (VII) may have the formula:

X¹, X², R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹, R¹², R¹³, R¹⁴, R¹⁵, R²⁵,and R²⁶ are as described herein, including embodiments thereof. R⁵ andR⁶ may independently be unsubstituted 3 to 5 membered cycloalkyl orR^(5a)-substituted or unsubstituted C₁-C₅ alkyl. R^(5a) may beunsubstituted 2 to 5 membered heteroalkyl or 5 to 6 memberedheterocycloalkyl. R^(5a) may be —N(CH₃)₂ or unsubstituted morpholino. R¹may be —CN. R¹ may be —COOCH₃. R¹ may be unsubstituted methyl. R² may beC₁-C₃ unsubstituted alkyl. When R¹ is —CN, R² may be unsubstitutedmethyl. R¹¹ may be hydrogen or halogen.

The compound of formula (X) may have the formula:

The compound of formula (VII) may have the formula:

X¹, X², R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, R¹², R¹³, R²⁵, and R²⁶ areas described herein, including embodiments thereof. R⁵ and R⁶ mayindependently be unsubstituted 3 to 5 membered cycloalkyl orR^(5a)-substituted or unsubstituted C₁-C₅ alkyl. R^(5a) may beunsubstituted 2 to 5 membered heteroalkyl or 5 to 6 memberedheterocycloalkyl. R^(5a) may be —N(CH₃)₂ or unsubstituted morpholino. R¹may be —CN. R¹ may be —COOCH₃. R¹ may be unsubstituted methyl. R² may beC₁-C₃ unsubstituted alkyl. When R¹ is —CN, R² may be unsubstitutedmethyl. R¹¹ may be hydrogen or halogen.

The compound of formula (XI) may have the formula:

The compound of formula (VII) may have the formula:

X¹, X², R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, R¹², R¹³, R²⁵, and R²⁶ areas described herein, including embodiments thereof. R⁵ and R⁶ mayindependently be unsubstituted 3 to 5 membered cycloalkyl orR^(5a)-substituted or unsubstituted C₁-C₅ alkyl. R^(5a) may beunsubstituted 2 to 5 membered heteroalkyl or 5 to 6 memberedheterocycloalkyl. R^(5a) may be —N(CH₃)₂ or unsubstituted morpholino. R¹may be —CN. R¹ may be —COOCH₃. R¹ may be unsubstituted methyl. R² may beC₁-C₃ unsubstituted alkyl. When R¹ is —CN, R² may be unsubstitutedmethyl. R¹¹ may be hydrogen or halogen.

The compound of formula (XII) may have the formula:

In another aspect is a compound having formula:

R¹, R², R³, R⁴, R⁵, R⁶, R¹⁶, and R¹⁸ are as described herein, includingembodiments thereof.

The compound of formula (XIII) may have the formula:

The compound of formula (XIV) may have the formula:

The compound of formula (XIII) may have the formula:

The compound of formula (XV) may have the formula:

The compound of formula (XIII) may have the formula:

The compound of formula (XVI) may have the formula:

The compound of formula (XIII) may have the formula:

The compound of formula (XVII) may have the formula:

The compound of formula (XIII) may have the formula:

The compound of formula (XVIII) may have the formula:

In embodiments, R² of the compounds provided herein (e.g. formula (VII),(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), or(XVII), including embodiments thereof) is a polar substituent. Inembodiments, R² of the compounds provided herein (e.g. formula (VII),(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), or(XVII), including embodiments thereof) is N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H,—SO₂Ph, —SO₂NH₂, —NHNH₂, —ONH₂, R^(2a)-substituted or unsubstitutedC₁-C₃ alkyl, or 1 to 3 membered R^(2a)-substituted or unsubstitutedheteroalkyl. R^(2a) may be —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂Ph,—SO₂NH₂, —NHNH₂, —ONH₂, R^(2b)-substituted or unsubstituted C₁-C₅ alkyl,R^(2b)-substituted or unsubstituted 2 to 5 membered heteroalkyl,R^(2b)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(2b)-substituted or unsubstituted 5 or 6 membered aryl, orR^(2b)-substituted or unsubstituted 5 or 6 membered heteroaryl. R^(2b)may be halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, unsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 memberedheteroalkyl, unsubstituted 3 to 8 membered cycloalkyl, unsubstituted 3to 6 membered heterocycloalkyl, unsubstituted 5 to 6 membered aryl, orunsubstituted 5 to 6 membered heteroaryl.

In embodiments, R² of the compounds provided herein (e.g. formula (VII),(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), or(XVII), including embodiments thereof) is R^(2a)-substituted orunsubstituted C₁-C₃ alkyl, or 1 to 3 membered R^(2a)-substituted orunsubstituted heteroalkyl, where R^(2a) is unsubstituted 3 to 6 memberedheterocycloalkyl, unsubstituted 5 or 6 membered aryl, or unsubstituted 5or 6 membered heteroaryl. In embodiments, R² of the compounds providedherein (e.g. formula (VII), (VIII), (IX), (X), (XI), (XII), (XIII),(XIV), (XV), (XVI), (XVII), or (XVII), including embodiments thereof) isunsubstituted methyl or unsubstituted methoxy. In embodiments, R^(2a) ofthe compounds provided herein (e.g. formula (VII), (VIII), (IX), (X),(XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), or (XVII), includingembodiments thereof) is unsubstituted pyridine.

In embodiments, R⁵ and R⁶ of the compounds provided herein (e.g. formula(VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI),(XVII), or (XVII), including embodiments thereof) are independentlyhydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,unsubstituted alkyl, or unsubstituted cycloalkyl. In embodiments, R⁵ andR⁶ of the compounds provided herein (e.g. formula (VII), (VIII), (IX),(X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), or (XVII),including embodiments thereof) are independently hydrogen, C₁-C₃unsubstituted alkyl or 3 to 5 membered cycloalkyl. In embodiments, R⁵and R⁶ of the compounds provided herein (e.g. formula (VII), (VIII),(IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), or (XVII),including embodiments thereof) are independently hydrogen, unsubstitutedmethyl, unsubstituted ethyl, unsubstituted allyl, or unsubstitutedcyclopropyl.

In embodiments, R¹ of the compounds provided herein (e.g. formula (VII),(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), or(XVII), including embodiments thereof) is —CN or unsubstitutedheteroalkyl. In embodiments, R¹ of the compounds provided herein (e.g.formula (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV),(XVI), (XVII), or (XVII), including embodiments thereof) is —CN.

In embodiments, the compounds provided herein are prodrugs as describedherein, including embodiments thereof. Such prodrugs may take the formof formula (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV),(XVI), (XVII), or (XVII), including embodiments thereof. In embodiments,the prodrugs described herein exist in an inactive form whereupon thecompound may be converted to an active form in vivo. Prodrugs may alsobe converted to an active form ex-vivo prior to administration (e.g. bychemical modification of the prodrug prior to delivery).

In embodiments, the compounds provided herein inhibit HMT SUV39H1activity. In embodiments, the compounds provided herein specificallyinhibit HMT SUV39H1 activity (e.g. relative to other HMT's such as oneor more of G9a, DOT1, EZH1, EZH2, GLP, MLL1, MLL2, MLL3, MLL4, NSD2,SET1b, SET7/9, SET8, SETMAR, SMYD2, SUV39H2). The inhibition may be atleast about 2, 3, 4, 5, 10, 100, or 1000 fold greater inhibitionrelative to inhibition of other HMT's such as one or more of G9a, DOT1,EZH1, EZH2, GLP, MLL1, MLL2, MLL3, MLL4, NSD2, SET1b, SET7/9, SET8,SETMAR, SMYD2, SUV39H2. In embodiments, the inhibition of SUV39H1 may beat least 2 fold greater than the inhibition of other HMTs describedherein. In embodiments, the inhibition of SUV39H1 may be at least 3 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of SUV39H1 may be at least 4 fold greaterthan the inhibition of other HMTs described herein. In embodiments, theinhibition of SUV39H1 may be at least 5 fold greater than the inhibitionof other HMTs described herein. In embodiments, the inhibition ofSUV39H1 may be at least 6 fold greater than the inhibition of other HMTsdescribed herein. In embodiments, the inhibition of SUV39H1 may be atleast 7 fold greater than the inhibition of other HMTs described herein.In embodiments, the inhibition of SUV39H1 may be at least 8 fold greaterthan the inhibition of other HMTs described herein. In embodiments, theinhibition of SUV39H1 may be at least 9 fold greater than the inhibitionof other HMTs described herein. In embodiments, the inhibition ofSUV39H1 may be at least 10 fold greater than the inhibition of otherHMTs described herein.

In embodiments, the inhibition of SUV39H1 may be at least 10 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of SUV39H1 may be at least 20 fold greaterthan the inhibition of other HMTs described herein. In embodiments, theinhibition of SUV39H1 may be at least 30 fold greater than theinhibition of other HMTs described herein. In embodiments, theinhibition of SUV39H1 may be at least 40 fold greater than theinhibition of other HMTs described herein. In embodiments, theinhibition of SUV39H1 may be at least 50 fold greater than theinhibition of other HMTs described herein. In embodiments, theinhibition of SUV39H1 may be at least 60 fold greater than theinhibition of other HMTs described herein. In embodiments, theinhibition of SUV39H1 may be at least 70 fold greater than theinhibition of other HMTs described herein. In embodiments, theinhibition of SUV39H1 may be at least 80 fold greater than theinhibition of other HMTs described herein. In embodiments, theinhibition of SUV39H1 may be at least 90 fold greater than theinhibition of other HMTs described herein. In embodiments, theinhibition of SUV39H1 may be at least 100 fold greater than theinhibition of other HMTs described herein.

The compounds provided herein may inhibit HMT G9a activity. Thecompounds provided herein may specifically inhibiting HMT G9a activity(e.g. relative to other HMT's such as one or more of SUV39H1, DOT1,EZH1, EZH2, GLP, MLL1, MLL2, MLL3, MLL4, NSD2, SET1b, SET7/9, SET8,SETMAR, SMYD2, SUV39H2). The inhibition may be at least about 2, 3, 4,5, 10, 100, or 1000 fold greater inhibition relative to inhibition ofother HMT's such as one or more of SUV39H1, DOT1, EZH1, EZH2, GLP, MLL1,MLL2, MLL3, MLL4, NSD2, SET1b, SET7/9, SET8, SETMAR, SMYD2, SUV39H2. Inembodiments, the inhibition of G9A may be at least 2 fold greater thanthe inhibition of other HMTs described herein. In embodiments, theinhibition of G9A may be at least 3 fold greater than the inhibition ofother HMTs described herein. In embodiments, the inhibition of G9A maybe at least 4 fold greater than the inhibition of other HMTs describedherein. In embodiments, the inhibition of G9A may be at least 5 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of G9A may be at least 6 fold greater thanthe inhibition of other HMTs described herein. In embodiments, theinhibition of G9A may be at least 7 fold greater than the inhibition ofother HMTs described herein. In embodiments, the inhibition of G9A maybe at least 8 fold greater than the inhibition of other HMTs describedherein. In embodiments, the inhibition of G9A may be at least 9 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of G9A may be at least 10 fold greater thanthe inhibition of other HMTs described herein.

In embodiments, the inhibition of G9A may be at least 10 fold greaterthan the inhibition of other HMTs described herein. In embodiments, theinhibition of G9A may be at least 20 fold greater than the inhibition ofother HMTs described herein. In embodiments, the inhibition of G9A maybe at least 30 fold greater than the inhibition of other HMTs describedherein. In embodiments, the inhibition of G9A may be at least 40 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of G9A may be at least 50 fold greater thanthe inhibition of other HMTs described herein. In embodiments, theinhibition of G9A may be at least 60 fold greater than the inhibition ofother HMTs described herein. In embodiments, the inhibition of G9A maybe at least 70 fold greater than the inhibition of other HMTs describedherein. In embodiments, the inhibition of G9A may be at least 80 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of G9A may be at least 90 fold greater thanthe inhibition of other HMTs described herein. In embodiments, theinhibition of G9A may be at least 100 fold greater than the inhibitionof other HMTs described herein.

The compounds provided herein may also inhibiting both HMT SUV39H1 andthe activity of HMT G9a. The compounds provided herein may specificallyinhibiting both HMT SUV39H1 and the activity of HMT G9a (e.g. relativeto other HMT's such as one or more of DOT1, EZH1, EZH2, GLP, MLL1, MLL2,MLL3, MLL4, NSD2, SET1b, SET7/9, SET8, SETMAR, SMYD2, SUV39H2). Theinhibition may be at least about 2, 3, 4, 5, 10, 100, or 1000 foldgreater inhibition relative to inhibition of other HMT's such as one ormore of DOT1, EZH1, EZH2, GLP, MLL1, MLL2, MLL3, MLL4, NSD2, SET1b,SET7/9, SET8, SETMAR, SMYD2, SUV39H2. Thus, in embodiments, thecompounds provided herein are capable of specifically inhibiting H3K9dimethylation or trimethylation (e.g. relative to other epigeneticevents). The compounds provided herein may be capable of specificallyinhibiting H3K9 dimethylation. The compounds provided herein may becapable of specifically inhibiting trimethylation. The compoundsprovided herein may be capable of specifically inhibiting both H3K9dimethylation and H3K9 trimethylation.

In embodiments, the inhibition of SUV39H1 and G9a may be at least 2 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of SUV39H1 and G9a may be at least 3 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of SUV39H1 and G9a may be at least 4 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of SUV39H1 and G9a may be at least 5 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of SUV39H1 and G9a may be at least 6 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of SUV39H1 and G9a may be at least 7 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of SUV39H1 and G9a may be at least 8 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of SUV39H1 and G9a may be at least 9 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of SUV39H1 and G9a may be at least 10 foldgreater than the inhibition of other HMTs described herein.

In embodiments, the inhibition of SUV39H1 and G9a may be at least 10fold greater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of SUV39H1 and G9a may be at least 20 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of SUV39H1 and G9a may be at least 30 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of SUV39H1 and G9a may be at least 40 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of SUV39H1 and G9a may be at least 50 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of SUV39H1 and G9a may be at least 60 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of SUV39H1 and G9a may be at least 70 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of SUV39H1 and G9a may be at least 80 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of SUV39H1 and G9a may be at least 90 foldgreater than the inhibition of other HMTs described herein. Inembodiments, the inhibition of SUV39H1 and G9a may be at least 100 foldgreater than the inhibition of other HMTs described herein.

In embodiments, a compound herein (e.g. formula (VII), (VIII), (IX),(X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), or (XVII),including embodiments thereof) is an epigenetic inhibitor. Inembodiments, the compound inhibits H3K9 trimethylation or dimethylation.

In certain embodiments the compound is a compound as set forth in Table1.

TABLE 1 Exemplary embodiments of compounds provided herein. Refer-Structure ence

ETP6

ETP8

ETP12

ETP14

ETP27

ETP49

ETP56

ETP69

ETP95

ETP100

ETP120

ETP125

ETP128

ETP130

ETP154

ETP167

ETP178

ETP195

ETP204

ETP206

ETP214

ETP218

ETP223

ETP229

ETP303

ETP309

ETP313

ETP328

ETP331

ETP341

ETP344

ETP356

ETP359

ETP365

ETP382

ETP384

ETP390

ETP406

ETP417

ETP422

ETP425

ETP442

ETP450

ETP452

ETP469

ETP484

ETP493

III. Pharmaceutical Compositions

In another aspect a pharmaceutical composition is provided. Thepharmaceutical composition includes a compound as provided herein (e.g.of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), or (XVIII)) and apharmaceutically acceptable excipient. The compound may be provided in atherapeutically effective amount (e.g. for treating cancer as describedherein). The compound may be provided as a prodrug, as described herein,including embodiments thereof. When provided as a prodrug, the prodrugbe converted to an active form in-vivo or ex-vivo according to themethods described herein.

In another aspect, a pharmaceutical composition is provided including acompound as provided herein (e.g. of formula (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV),(XVI), (XVII), or (XVIII)), a pharmaceutically acceptable excipient, andan additional anticancer agent. The anticancer agent may be anepigenetic inhibitor or a multi-kinase inhibitor. The epigeneticinhibitor may be a DNA methyltransferase (DNMT) inhibitor. Theepigenetic inhibitor may be azacitidine or decitabine. The multi-kinaseinhibitor may include a single kinase inhibitor. The multi-kinaseinhibitor may be sorafenib. In embodiments the pharmaceuticalcomposition includes more than one multi-kinase inhibitor or more thanone epigenetic inhibitor and a compound as provided herein (e.g. offormula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), or (XVIII)). Inembodiments the pharmaceutical composition includes a compound asprovided herein (e.g. of formula (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI),(XVII), or (XVIII)), a pharmaceutically acceptable excipient, at leastone multi-kinase inhibitor (e.g. a single kinase inhibitor), and atleast one epigenetic inhibitor. In embodiments, the epigeneticinhibitor, DNMT inhibitor, multi-kinase inhibitor and single kinaseinhibitor are anti-cancer agents. The anti-cancer agents include thosedescribed herein and embodiments thereof.

The pharmaceutical composition may include a first amount of a compoundas described herein, including embodiments thereof, and a second amountof the multi-kinase inhibitor. The first amount and second amount may betogether an effective amount to provide a synergistic therapeutic effect(e.g. the measured effect of compounds administered in combination isgreater than the sum of the individual effects of each of the compoundsadministered alone as a single agent). The multi-kinase inhibitor may besorafenib. The pharmaceutical composition of may include a first amountof a compound as described herein, including embodiments thereof, and asecond amount of the epigenetic inhibitor, wherein the first amount andsecond amount are together an effective amount to provide a synergistictherapeutic effect. The epigenetic inhibitor may be azacitidine ordecitabine.

The multi-kinase inhibitor of pharmaceutical composition may bedasatinib, sunitinib, erlotinib, bevacizumab, vatalanib, vemurafenib,vandetanib, cabozantinib, poatinib, axitinib, ruxolitinib, regorafenib,crizotinib, bosutinib, cetuximab, gefitinib, imatinib, lapatinib,lenvatinib, mubritinib, nilotinib, panitumumab, pazopanib, trastuzumab,or sorafenib. The multi-kinase inhibitor of the pharmaceuticalcomposition may be sorafenib. The epigenetic inhibitor may beazacitidine or decitadine. The epigenetic inhibitor may be azacitidine.The epigenetic inhibitor may be decitadine. In some dosage forms, thecompound and the multi-kinase inhibitor or the epigenetic inhibitor maybe co-administered as a single dosage form.

The pharmaceutical compositions described herein, including embodimentsthereof may be used in the treatment of cancers. The pharmaceuticalcompositions described herein, including embodiments thereof may be usedin the treatment of solid and blood tumors, including ovarian cancer,breast cancer, lung cancer, leukemia (e.g. AML or CML), lymphoma,pancreatic cancer, kidney cancer, melanoma, liver cancer, colon cancer,sarcoma, multiple myeloma, brain cancer or prostate cancer. Thepharmaceutical compositions described herein, including embodimentsthereof may be used in the treatment of non-small cell lung cancer. Thepharmaceutical composition of may be used in the treatment of coloncancer. The pharmaceutical composition of may be used in the treatmentof AML. The pharmaceutical composition of may be used in the treatmentof CML. The pharmaceutical composition of may be used in the treatmentof ovarian cancer. The pharmaceutical composition of may be used in thetreatment of melanoma. The pharmaceutical composition of may be used inthe treatment of breast cancer. The pharmaceutical composition of may beused in the treatment of prostate cancer. The pharmaceutical compositionof may be used in the treatment of pancreatic cancer. The pharmaceuticalcomposition of may be used in the treatment of liver cancer.

IV. Methods

In another aspect a method of treating cancer is provided. The methodincludes administering to a subject in need thereof a therapeuticallyeffective amount of a compound of formula (I), (II), (III), (IV), (V),(VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI),(XVII), or (XVIII)), including embodiments thereof. In embodiments, thetherapeutically effective amount is of a compound having formula (I),(II), (III), (IV), (V), (VI), or (VII), including embodiments thereof.The compound may have formula (I). The compound may have formula (II).The compound may have formula (III). The compound may have formula (IV).The compound may have formula (V). The compound may have formula (VI).The compound may have formula (VII). The compound may be a compound asset forth in Table 1. In embodiments, the compound is formulated as apharmaceutical composition as described herein, including embodimentsthereof.

The cancer may be a solid and blood tumor, including ovarian cancer,breast cancer, lung cancer, leukemia (e.g. AML or CML), lymphoma,pancreatic cancer, kidney cancer, melanoma, liver cancer, colon cancer,sarcoma, multiple myeloma, brain cancer or prostate cancer. The cancermay be ovarian cancer. The cancer may be lung cancer. The lung cancermay be non-small cell lung cancer. The cancer may be pancreatic cancer.The cancer may be kidney cancer. The cancer may be melanoma. The cancermay be liver cancer. The cancer may be colon cancer. The cancer may bebrain cancer. The cancer may be prostate cancer. The cancer may be asarcoma. The cancer may be a leukemia. The leukemia may be CML. Thecancer may be AML. In embodiments the cancer being treated is AML,wherein the AML expresses Flt3 kinase protein.

In embodiments, the cancer is caused by misregulation of a histonemethyltransferase (HMT). The misregulation may be overexpression,downregulation, intragenic mutation, translocation or promotor DNAmethylation. The HMT may be SUV39H1/2 (KMT1A/B), G9a (KMT1C), MLL1(KMT2A), MLL4 (KMT2D), SMYD3, DOT1L (KMT4), SET8/PR-SET7 (KMT5A) or EZH2(KMT6). In embodiments, the HMT is SUV39H1/2 (KMT1A/B). In embodiments,the HMT is SUV39H1.

The method may also include administering an additional anticanceragent. The anticancer agent may be an epigenetic inhibitor or amulti-kinase inhibitor. The administration may include a first amount ofthe compound and a second amount of the epigenetic inhibitor, whereinthe first amount and second amount are together an effective amount toprovide a synergistic therapeutic effect. The epigenetic inhibitor maybe azacitidine or decitadine. The compound and the epigenetic inhibitormay be co-administered as a pharmaceutical composition. In certainembodiments the epigenetic inhibitor is a DNMT inhibitor. Theadministration of the pharmaceutical compound may be useful in treatingovarian cancer. The administration of the pharmaceutical compound may beuseful in treating lung cancer. The lung cancer may be non-small celllung cancer.

The method may include administering a first amount of the compound anda second amount of the multi-kinase inhibitor, wherein the first amountand second amount are together an effective amount to provide asynergistic therapeutic effect. The multi-kinase inhibitor may besorafenib. The compound and the multi-kinase inhibitor may beco-administered as a pharmaceutical composition. The administration ofthe pharmaceutical compound may be useful in treating ovarian cancer.The administration of the pharmaceutical compound may be useful intreating lung cancer. The lung cancer may be non-small cell lung cancer.

In embodiments, the methods of treatment described herein yield asuppression of tumor growth. The suppressed tumor growth may indicatethe absence of toxicity symptoms (e.g. body weight loss). Those skilledin the art understand that body weight loss observed during may cancertreatments is a result of toxicity associated with the treatment (e.g.killing of healthy tissue). Accordingly, the compounds described hereinmay provide effective therapeutic value without toxicity issues normallyassociated with cancer treatments.

Compounds described herein, including embodiments thereof, may beadministered in as a therapeutically effective amount. The compound maybe administered in any effective size dose or effect dosage regimen(e.g. one dose daily). A therapeutically effective dose may bedetermined by one of skill in the art using methods described herein andthose known in the art.

In another aspect, a method of inhibiting a histone methyltransferase(HMT) is provided. The method includes contacting a methyltransferasewith a compound provided herein (a compound of formula (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV),(XV), (XVI), (XVII), or (XVIII)), including embodiments thereof). Inembodiments, the histone methyltransferase is a lysine-specific HMT. Inembodiments, the histone methyltransferase is an arginine-specific HMT.The HMT may be SUV39H1/2 (KMT1A/B), G9a (KMT1C), MLL1 (KMT2A), MLL4(KMT2D), SMYD3, DOT1L (KMT4), SET8/PR-SET7 (KMT5A) or EZH2 (KMT6). Inembodiments, the HMT is SUV39H1/2 (KMT1A/B). In embodiments, the HMT isSUV39H1. In embodiments, the method of inhibiting is performed in vitro.

In embodiments, the HMT is within a cell. Thus, in embodiments, the cellis within an organism.

In another aspect, a method of inhibiting growth of a cancer cell invivo is provided. The method includes contactin a cancer cell with acompound provided herein (a compound of formula (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV),(XVI), (XVII), or (XVIII)), including embodiments thereof). The cancercell may be derived from a solid and blood tumor, including ovariancancer, breast cancer, lung cancer, leukemia (e.g. AML or CML),lymphoma, pancreatic cancer, kidney cancer, melanoma, liver cancer,colon cancer, sarcoma, multiple myeloma, brain cancer or prostatecancer. The cancer cell may be an ovarian cancer cell. The cancer cellmay be a lung cancer cell. The lung cancer cell may be a non-small celllung cancer cell. The cancer cell may be pancreatic cancer cell. Thecancer cell may be a kidney cancer cell. The cancer cell may be amelanoma cell. The cancer cell may be a liver cancer cell. The cancercell may be a colon cancer cell. The cancer cell may be a brain cancercell. The cancer cell may be a prostate cancer cell. The cancer cell maybe a sarcoma cell. The cancer cell may be a leukemia cell. The leukemiacell may be a CML cell. The cancer cell may be an AML cell. Inembodiments the cancer cell is an AML cell, wherein the AML cellexpresses Flt3 kinase protein.

V. Examples Example 1

The compounds of Formulae I-XVIII can be prepared in a number of wayswell known to those skilled in the art, including both solid phase andsolution phase techniques. The compounds can be synthesized, forexample, by the methods described below, or variations thereof asappreciated by the skilled artisan. Although these syntheses areillustrated for preparation of ETPs having substituted aryl substituentsat C6, identical sequences can be employed to prepare ETPs withsubstituted heteroaryl substituents at C6. See e.g. Martins, M. M.;Carvalho Tetrahedron 2007, 63, 9923-9932; Borthwick, A. D. Chem Rev2012, 112, 3641-3716; Iwasa, E.; Hamashima, Y.; Sodeoka, M. Isr. J.Chem. 2011, 51, 420-433; Nicolaou, K. C.; Lu, M.; Totokotsopoulos, S.;Heretsch, P.; Giguère, D.; Sun, Y.-P.; Sarlah, D.; Nguyen, T. H.; Wolf,I. C.; Smee, D. F.; Day, C. W.; Bopp, S.; Winzeler, E. A. J. Am. Chem.Soc. 2012, 134, 17320-17332. All processes disclosed in association withthe present invention are contemplated to be practiced on any scale,including milligram, gram, multigram, kilogram, multikilogram orcommercial industrial scale.

Embodiments of Formula I may be prepared as shown in Scheme 1 above.Dehydrative condensation of an aldehyde with a glycine derivativerenders an intermediate imine such as 1, which when treated with base inthe presence of lithium bromide generates an azomethine ylide thatsubsequently undergoes a dipolar cycloaddition reaction to generate thedesired pyrrolidine product such as 2. The azomethine ylide can begenerated and the cycloaddition accomplished in many ways known in theart (Grigg, R. and V. Sridharan (1993). Azomethine Ylide Cycloadditionsvia 1,2-Prototropy and Metallo-Dipole Formation from Imines. Advances inCycloaddition. D. P. Curran. Greenwich, Conn., Jai Press Inc. 3:161-204). For example, the cycloaddition may be carried out by simplyheating the components in a solvent or by the use of other metalcomplexes or salts and other bases. Compounds 2 are typically generatedas mixtures of diasteroisomers, the isomer exemplified by 2 can beseparated from the mixture based on its reduced solubility in solventmixtures like MeOH/DCM (1:1). If required, the diastereoisomer productscan be obtained in high purity by column chromatography; the subsequentsteps can be performed with the separated stereoisomers or carried outwith the mixture of stereoisomers with separation being accomplished bycolumn chromatography, crystallization or other common techniques afterthe polysulfur bridge is incorporated.

The product of this cycloaddition reaction is a pyrrolidine ester, whichcan be converted to a dioxopiperazine in many well-known ways (Martins,M. B., Ivone, C. (2007) Diketopiperazines: biological activity andsynthesis. Tetrahedron 63, 9923-9932). For example, the pyrrolidineester can be acylated on the free nitrogen with an α-halo acid chlorideto yield the corresponding amide. These compounds can be treated with anexcess of a primary amine to undergo a cyclocondensation reactionfurnishing the desired diketopiperazine ring, compounds, exemplified by3 and 4. In general the diketopiperazine was isolated as mixture ofdiastereoisomers which need not be separated at this stage.Alternatively, the pyrrolidine ester can be coupled with an α-aminoester(typically protected on nitrogen) to give a dipeptide, which directly orupon removal of the nitrogen-protecting group can be cyclized to thedioxopiperazine intermediate.

The diketopiperazine then undergoes a sulfidation process, one exampleof which is illustrated in Scheme 1, to yield the desired ETP.Alternatively, the intermediate in this sequence, can be reduced and thedithiol product protected on the two sulfur atoms. The conversion of thediooxopiperazine intermediate to an ETP product can be accomplished inmany ways well known in the art (Iwasa, E.; Hamashima, Y.; Sodeoka, M.(2011) Epipolythiodiketopiperazine Alkaloids: Total Syntheses andBiological Activities Isr. J. Chem. 51, 420-433. Nicolaou, K. C., et al.(2011) Synthesis and Biological Evaluation of Epidithio-, Epitetrathio-,and bis-(Methylthio)diketopiperazines: Synthetic Methodology,Enantioselective Total Synthesis of Epicoccin G, 8,8′-epi-ent-RostratinB, Gliotoxin, Gliotoxin G, Emethallicin E, and Haematocin and Discoveryof New Antiviral and Antimalarial Agents J. Am. Chem. Soc., 133,8150-8153.)

Synthetic scheme for enantioselective synthesis of ETP analoguesdescribed herein.

To a stirred solution of racemic 1 (2.1 g, 7 mmol) in CH₂Cl₂ (14 mL)were added Et₃N (1.4 g, 14 mmol) and acyl chloride 2 (3.25 g, 10 mmol)in CH₂Cl₂ (14 mL) at 0° C. The reaction was stirred overnight. Thereaction was quenched with sat. NaHCO₃ and extracted with CH₂Cl₂. Thecombined organic layer was dried over MgSO₄ and evaporated to dryness.The crude product was purified by silica gel column chromatography byelution with 33% EtOAc/Hexane to afford 1.9 g (46%) of compound 3 and1.7 g (40%) of compound 4. For compound 3: ¹H NMR (400 MHz, CDCl₃) δ/ppm7.75 (d, 2H, J=7.4 Hz), 7.55 (d, 2H, J=7.4 Hz), 7.40 (t, 2H, J=7.4 Hz),7.30 (t, 2H, J=7.4 Hz), 7.30 (s, 1H), 7.19 (dd, 1H, J=1.4, 8.0 Hz), 6.86(d, 2H, J=7.8 Hz), 6.00 (d, 2H, J=6.6 Hz), 5.22 (s, 1H), 5.19 (d, 2H,J=7.8 Hz), 4.60 (dd, 1H, J=7.4, 9.8 Hz), 4.39-4.22 (m, 4H), 4.20-4.14(m, 2H), 2.59 (dd, 1H, J=9.8, 13.8 Hz), 2.35 (dd, 1H, J=7.0, 13.8 Hz),1.61 (s, 3H), 1.35 (t, 3H, J=7.0 Hz), 0.98 (d, 3H, J=7.0 Hz); ¹³C NMR(100 MHz, CDCl₃) δ/ppm 174.0, 170.2, 156.1, 148.31, 148.27, 143.70,143.65, 141.3, 131.8, 127.75, 127.72, 127.0, 125.1, 125.0, 121.3, 120.0,108.6, 107.8, 101.4, 70.3, 67.2, 61.9, 58.2, 47.8, 47.0, 44.5, 37.3,24.3, 17.4, 14.1;

For compound 4 (main rotamer): ¹H NMR (400 MHz, CDCl₃) δ/ppm 7.75 (d,2H, J=7.4 Hz), 7.55 (d, 2H, J=7.4 Hz), 7.40 (t, 2H, J=7.4 Hz), 7.30 (t,2H, J=7.4 Hz), 7.30 (s, 1H), 7.19 (dd, 1H, J=1.4, 8.0 Hz), 7.03 (s, 1H),6.93 (d, 1H, J=7.8 Hz), 6.80 (d, 1H, J=8.2 Hz), 5.95 (d, 2H, J=2.2 Hz),5.37 (dd, 1H, J=3.4, 8.2 Hz), 5.27 (d, 1H, J=7.6 Hz), 4.76 (s, 1H),4.40-4.10 (m, 6H), 2.90 (dd, 1H, J=3.4, 13.2 Hz), 2.41 (dd, 1H, J=2.3,13.2 Hz), 1.62 (s, 3H), 1.40 (d, 3H, J=7.0 Hz), 1.39 (t, 3H, J=7.0 Hz);¹³C NMR (100 MHz, CDCl₃) δ/ppm 174.0, 170.9, 156.3, 147.9, 147.7,143.64, 143.62, 141.3, 130.6, 127.8, 127.7, 127.0, 125.1, 125.0, 120.2,120.0, 108.3, 107.0, 101.1, 70.8, 67.2, 62.6, 59.3, 48.4, 47.0, 43.4,40.8, 23.1, 17.8, 14.1;

To a stirred solution of compound 3 (2.8 g, 4.7 mmol) in CH₂Cl₂ (18 mL)was added piperidine (4.0 g, 47 mmol). After 30 min, the solvent wasremoved. The crude product was purified by silica gel columnchromatography by elution with 3% MeOH/CH₂Cl₂ to afford 1.4 g (91%) ofcompound 5 as white solid. ¹H NMR (400 MHz, CDCl₃) δ/ppm 6.79 (d, 2H,J=7.8 Hz), 6.63 (dd, 1H, J=2.0, 8.2 Hz), 6.57 (d, 2H, J=2.0 Hz), 5.96(s, 2H), 5.91 (s, 1H), 4.87 (s, 1H), 4.43 (dd, 1H, J=6.6, 11.0 Hz), 4.17(q, 1H, J=6.6 Hz), 2.82 (dd, 1H, J=11.4, 13.4 Hz), 2.35 (dd, 1H, J=6.6,13.4 Hz), 1.68 (s, 3H), 1.44 (d, 3H, J=6.6 Hz); ¹³C NMR (100 MHz, CDCl₃)δ/ppm 168.9, 166.9, 148.3, 148.2, 130.8, 119.7, 108.7, 106.2, 101.4,69.3, 57.5, 51.6, 42.8, 35.8, 25.3, 15.4;

To a stirred solution of compound 5 (1.4 g, 4.3 mmol) in THF (43 mL) wasadded NaH (60%, 260 mg, 6.5 mmol) at 0° C. After 20 min at 23° C., MeI(1.85 g, 13 mmol) was added at 0° C. After 2 h at 23° C., the reactionwas quenched with sat. NH4Cl. The solvent was removed and the residuewas extracted with CH₂Cl₂. The combined organic layer was dried overMgSO₄ and evaporated to dryness. The crude product was purified bysilica gel column chromatography by elution with 25% EtOAc/Hexane toafford 1.25 g (86%) of compound 6. ¹H NMR (400 MHz, CDCl₃) δ/ppm 6.82(d, 2H, J=8.2 Hz), 6.73 (d, 1H, J=2.0 Hz), 6.71 (s, 1H), 5.98 (s, 2H),4.73 (dd, 1H, J=6.2, 10.6 Hz), 3.88 (q, 1H, J=7.0 Hz), 3.01 (s, 3H),2.93 (dd, 1H, J=6.2, 13.0 Hz), 2.26 (dd, 1H, J=10.6, 13.0 Hz), 1.60 (s,3H), 1.54 (d, 3H, J=7.4 Hz); ¹³C NMR (100 MHz, CDCl₃) δ/ppm 165.9,165.2, 148.2, 148.1, 129.3, 120.3, 119.4, 108.6, 106.1, 101.4, 70.2,60.6, 58.4, 44.1, 41.6, 32.1, 22.7, 16.7;

To a suspension of elemental sulfur (300 mg, 9.4 mmol) in dry THF (10mL) NaHMDS (0.6 M in toluene, 7.40 mL) is being added dropwise. Theresulting yellow reaction mixture is stirred at ambient temperature forone minute and then combined with a slurry of the substrate 6 (340 mg,1.0 mmol in 5 mL dry THF). A second portion of NaHMDS (0.6 M in toluene,4.8 mL) is subsequently added resulting in an orange mixture which isstirred at ambient temperature for 30 minutes. After quenching withsaturated aqueous ammonium chloride, the solvent was removed and theresidue was extracted with CH₂Cl₂. The combined organic layer was driedover MgSO₄ and evaporated to dryness. The crude product was purified bysilica gel column chromatography by elution with 2% EtOAc/CH₂Cl₂ toafford 129 mg (32%) of compound 7. ¹H-NMR (400 MHz, CDCl₃): δ/ppm 6.96(s, 1H), 6.91 (s, 2H), 6.06 (s, 2H), 4.89 (s, 1H), 3.36 (d, 1H, J=14.5Hz), 3.14 (s, 3H), 3.06 (d, 1H, J=14.5 Hz), 2.00 (s, 3H), 1.73 (s, 3H);¹³C-NMR (100 MHz, CDCl₃): δ/ppm 165.6, 162.1, 148.6, 148.3, 127.5,120.7, 120.3, 108.6, 107.2, 101.6, 73.4, 73.3, 72.4, 44.4, 42.8, 27.8,24.8, 18.1. ^(α)[D]₂₀=+2400, ee %>99%.

See procedure as preparing compound 5. ¹H NMR (400 MHz, DMSO-d₆) δ/ppm8.45 (d, 1H, J=4.2 Hz), 6.88 (d, 1H, J=8.2 Hz), 6.70 (s, 1H), 6.60 (d,1H, J=7.4 Hz), 6.00 (s, 2H), 4.87 (s, 1H), 4.73 (dd, 1H, J=6.6, 11.0Hz), 3.78-3.70 (m, 1H), 2.42-2.26 (m, 2H), 1.62 (s, 3H), 1.35 (d, 3H,J=7.4 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ/ppm 168.6, 167.6, 147.7, 147.4,133.2, 121.4, 119.8, 108.6, 107.1, 101.7, 68.3, 55.8, 53.5, 42.6, 36.1,24.4, 18.8;

See procedure as preparing compound 6. ¹H-NMR (400 MHz, CDCl₃): δ/ppm6.79 (d, 1H, J=9.0 Hz), 6.63 (d, 1H, J=9.0 Hz), 6.57 (s, 1H), 5.96 (s,2H), 4.82 (s, 1H), 4.36 (dd, 1H, J=6.5, 11.0 Hz), 3.90 (q, 1H, J=7.0Hz), 3.04 (s, 3H), 2.76 (t, 1H, J=7.0 Hz), 2.45 (dd, 1H, J=6.5, 13.5Hz), 1.66 (s, 3H), 1.47 (d, 3H, J=7.0 Hz); ¹³C-NMR (100 MHz, CDCl₃):δ/ppm 166.6, 166.0, 148.2, 148.1, 130.8, 119.9, 119.8, 108.6, 106.2,101.4, 69.6, 60.8, 56.1, 42.6, 36.7, 32.0, 25.1, 15.3;

See procedure as preparing compound 7. ¹H-NMR (400 MHz, CDCl₃): δ/ppm6.96 (s, 1H), 6.91 (s, 2H), 6.06 (s, 2H), 4.89 (s, 1H), 3.36 (d, 1H,J=14.5 Hz), 3.14 (s, 3H), 3.06 (d, 1H, J=14.5 Hz), 2.00 (s, 3H), 1.73(s, 3H); ¹³C-NMR (100 MHz, CDCl₃): δ/ppm 165.6, 162.1, 148.6, 148.3,127.5, 120.7, 120.3, 108.6, 107.2, 101.6, 73.4, 73.3, 72.4, 44.4, 42.8,27.8, 24.8, 18.1. ^(α)[D]₂₀=−216°, ee %>95%.

Example 2 General Procedure for the Synthesis of PolyfunctionalizedPyrrolidine Esters Dimethylrac-(2S,4S,5S)-5-(4-Fluorophenyl)-4-methylpyrrolidine-2,4-dicarboxylate

4-Fluorobenzaldehyde (1.24 g, 10 mmol) was dissolved in 15 mL of MeCNcontaining triethylamine (1.5 mL, 11 mmol) and glycine methyl esterhydrochloride (1.35 g, 11 mmol). The reaction mixture was stirred for 5h at room temperature. After removing the solvent in vacuo, the solidresidue was re-dissolved in CH₂Cl₂ and washed twice from water to givethe imine intermediate as colourless oil. To a solution of this materialin 20 mL of THF, solid LiBr (1.1 g, 12 mmol) and triethylamine (1.7 mL,12 mmol) were added portionwise. After 2 min, methyl methacrylate (1.5g, 15 mmol) was added and the resulting solution was stirred at roomtemperature for 8 h. After evaporation of the solvent in vacuo andextractive work-up (3 times, CH₂Cl₂/water), the desired product wasisolated as yellow oil (2.6 g, 90% yield, as a single diastereomer). Insome cases the cycloadduct was isolated as a mixture of C4 epimers,which were separated by crystallization or chromatography.

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.30 (2H, m), 7.03 (2H, t, J=8.5 Hz),4.09 (1H, s), 4.06 (1H, t, J=7.0 Hz), 3.86 (3H, s), 3.30 (3H, s), 2.95(1H, br. s, NH), 2.76 (1H, dd, J=7.0, 13.5 Hz), 2.14 (1H, dd, J=13.0,13.5 Hz), 1.43 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 174.6 (C), 174.3(C), 162.3 (C, J_(C-F)=245 Hz), 134.7 (C, J_(C-F)=3 Hz), 128.4 (2CH, d,J_(C-F)=8 Hz), 115.0 (2CH, d, J_(C-F)=21 Hz), 73.1 (CH), 58.8 (CH), 54.6(C), 52.3 (CH₃), 51.5 (CH₃), 41.1 (CH₂), 22.5 (CH₃). LR-MS: 295.96;HR-MS (ESI) calculated for C₁₅H₁₈NO₄FCl: 296.1298 (M+H⁺), found:296.1302.

2-Ethyl rac-4-Methyl(2S,4S,5S)-4-methyl-5-(pyridin-3-yl)pyrrolidine-2,4-dicarboxylate

Isolated as pale yellow oil, dr (diastereomer ratio) >9:1. ¹H-NMR (500MHz, CDCl₃): δ/ppm 8.26 (1H, s), 8.23 (1H, dd, J=1.5, 4.5 Hz), 7.45 (1H,dd, J=1.5, 8.0 Hz), 6.98 (1H, dd, J=4.5, 9.0 Hz), 4.00-4.12 (2H, m),3.85 (2H, s), 3.78 (1H, app. t, J=7.5 Hz), 2.99 (3H, s), 2.48 (1H, dd,J=8.0, 13.0 Hz), 1.86 (1H, dd, J=8.0, 13.0 Hz), 1.17 (3H, s), 1.07 (3H,t, J=7.0 Hz); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 173.9 (C), 173.3 (C),148.9 (CH), 148.6 (CH), 134.9 (C), 133.9 (CH), 122.8 (CH), 70.7 (CH),60.8 (CH₂), 58.5 (CH), 54.4 (C), 51.1 (CH₃), 40.3 (CH₂), 22.4 (CH₃),14.0 (CH₃). IR (film): ν/cm⁻¹ 3380, 2981, 2950, 1732, 1430, 1210, 1110,1029, 716. LR-MS: 293.1 (M+H⁺); HR-MS (ESI) calculated for C₁₅H₂₀N₂O₄Na:315.1321 (M+Na⁺), found: 315.1315.

2-Ethyl 4-Methylrac-(2S,4S,5S)-5-(5-Bromo-2-methoxyphenyl)-4-methylpyrrolidine-2,4-dicarboxylate

Isolated as brown oil (single diastereomer). ¹H-NMR (500 MHz, CDCl₃):δ/ppm 7.45 (1H, d, J=2.5 Hz), 7.28 (1H, dd, J=2.5, 9.0 Hz), 6.70 (1H, d,J=9.0 Hz), 4.45 (1H, s), 4.25 (2H, q, J=7.0 Hz), 3.96 (1H, app. t, J=8.0Hz), 3.74 (3H, s), 3.30 (3H, s), 2.72 (1H, dd, J=9.0, 13.0 Hz), 2.05(1H, dd, J=9.0, 13.0 Hz), 1.36 (3H, s), 1.24 (3H, t, J=7.0 Hz); ¹³C-NMR(125 MHz, CDCl₃): δ/ppm 174.7 (C), 173.4 (C), 156.3 (C), 131.1 (CH),130.4 (CH), 129.4 (C), 112.7 (C), 112.0 (CH), 66.8 (CH), 61.0 (CH₂),59.0 (CH₃), 55.4 (CH₃), 54.5 (C), 51.3 (CH), 41.7 (CH₂), 22.8 (CH₃),14.2 (CH₃). IR (film): ν/cm⁻¹ 3366, 2980, 2938, 2839, 2236, 1736, 1486,1252, 1202, 1134, 1028, 809. LR-MS: 389.0 (M+Na⁺); HR-MS (ESI)calculated for C₁₆H₁₉N₂O₃BrNa: 389.0477 (M+Na⁺), found: 389.0471.

4-(tert-Butyl) 2-Ethylrac-(2S,4S,5S)-5-(4-Fluorophenyl)-4-methylpyrrolidine-2,4-dicarboxylate

Isolated as yellow oil (dr>9:1). ¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.37(2H, dd, J=5.5, 8.0 Hz), 7.04 (2H, app. t, J=8.0 Hz), 4.31 (2H, q, J=7.0Hz), 4.08 (1H, s), 4.03 (1H, t, J=8.5 Hz), 2.69 (1H, br. s), 2.66 (1H,dd, J=9.0, 13.0 Hz), 2.12 (1H, dd, J=8.5, 13.0 Hz), 1.49 (3H, s), 1.36(3H, t, J=7.0 Hz), 1.13 (9H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 173.7(C), 173.4 (C), 162.3 (C, d, J=244 Hz), 135.9 (C), 128.9 (2CH, d, J=8Hz), 114.9 (2CH, d, J=21 Hz), 80.8 (C), 72.3 (CH), 61.2 (CH₂), 58.9(CH), 55.1 (C), 41.9 (CH₂), 27.6 (3CH₃), 24.3 (CH₃), 14.3 (CH₃). IR(film): ν/cm¹ 3368, 2979, 2935, 1724, 1511, 1369, 1224, 1154. LR-MS:352.2 M+H; HR-MS (ESI) calculated for C₁₉H₂₆NO₄FNa: 374.1743 (M+Na⁺),found: 374.1742.

Ethyl rac-(2S,4S,5S)-4-Cyano-4-methyl-5-phenylpyrrolidine-2-carboxylate

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.52 (2H, d, J=7.1 Hz), 7.41-7.34 (3H,m), 4.34-4.24 (2H, m), 3.98 (1H, dd, J=4.2, 9.7 Hz), 3.93 (1H, s), 2.90(1H, s), 2.82 (1H, dd, J=4.2, 13.6 Hz), 2.29 (1H, dd, J=9.6, 13.6 Hz),1.42 (3H, s), 1.34 (3H, t, J=7.1 Hz); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm173.0 (C), 136.5 (C), 128.9 (CH), 128.6 (2CH), 127.6 (2CH), 121.9 (C),72.4 (CH), 61.7 (CH₂), 57.3 (CH), 44.1 (C), 42.5 (CH₂), 22.0 (CH₃), 14.2(CH₃); IR (film): ν/cm⁻¹ 3348, 2980, 2234, 1734, 1454; LR-MS: 281.1[M+Na]⁺; HR-MS (ESI) calculated for C₁₅H₁₈N₂O₂Na: 281.1266, found:281.1263.

Ethylrac-(2S,4S,5S)-4-Cyano-5-(4-fluorophenyl)-4-methylpyrrolidine-2-carboxylate

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.52 (2H, dd, J=5.4, 8.7 Hz), 7.09 (2H,t, J=8.7 Hz), 4.34-4.24 (2H, m), 4.00 (1H, dd, J=4.2, 9.6 Hz), 3.95 (1H,s), 2.83 (1H, dd, J=4.2, 13.7 Hz), 2.82 (1H, s), 2.30 (1H, dd, J=9.6,13.7 Hz), 1.41 (3H, s), 1.34 (3H, t, J=7.1 Hz); ¹³C-NMR (125 MHz,CDCl₃): δ/ppm 172.9 (C), 163.2 (C, d, J=246 Hz), 132.4 (C), 129.4 (2CH,d, J=8 Hz), 121.8 (C), 115.7 (2CH, d, J=22 Hz), 71.7 (CH), 61.9 (CH₂),57.3 (CH), 44.0 (C), 42.2 (CH₂), 22.0 (CH₃), 14.3 (CH₃); IR (film):ν/cm⁻¹ 3348, 2982, 2235, 1736, 1605, 1510; LR-MS: 299.1 [M+Na]⁺; HR-MS(ESI) calculated for C₁₅H₁₇FN₂O₂Na: 299.1172, found: 299.1177.

Ethylrac-(2S,4S,5S)-5-(Benzo[d][1,3]dioxol-5-yl)-4-cyano-4-methylpyrrolidine-2-carboxylate

Isolated as brown oil (dr=3:2). ¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.12 (1H,s), 6.98 (1H, d, J=8.5 Hz), 6.83 (1H, d, J=8.5 Hz), 5.99 (2H, s), 4.31(2H, q, J=7.0 Hz), 3.98 (1H, dd, J=4.5, 9.5 Hz), 3.89 (1H, s), 2.83 (1H,dd, J=4.0, 13.5 Hz), 2.75 (1H, br. s), 2.29 (1H, dd, J=9.5, 13.5 Hz),1.44 (3H, s), 1.36 (3H, t, J=7.0 Hz); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm173.0 (C), 148.0 (C), 147.9 (C), 130.6 (C), 122.1 (C), 121.1 (CH), 108.2(CH), 107.9 (CH), 101.3 (CH₂), 72.1 (CH), 61.6 (CH₂), 57.0 (CH), 43.8(C), 42.1 (CH₂), 22.1 (CH₃), 14.2 (CH₃). IR (film): ν/cm⁻¹ 3361, 2984,2900, 2254, 1734, 1490, 1447, 1265, 1041, 909. LR-MS: 325.1 M+Na⁺; HR-MS(ESI) calculated for C₁₆H₁₈N₂O₄Na: 325.1164 (M+Na⁺), found: 325.1161.

Ethylrac-(2S,4S,5R)-5-(6-Bromobenzo[d][1,3]dioxol-5-yl)-4-cyano-4-methylpyrrolidine-2-carboxylate

Isolated as brown oil (single diastereomer). ¹H-NMR (500 MHz, CDCl₃):δ/ppm 7.48 (1H, s), 6.96 (1H, s), 5.97 (1H, s), 5.92 (1H, s), 4.56 (1H,s), 4.20 (2H, q, J=7.0 Hz), 4.00 (1H, m), 2.67 (1H, dd, J=6.0, 8.0 Hz),2.65 (1H, broad s), 2.27 (1H, dd, J=9.0, 13.5 Hz), 1.53 (3H, s), 1.27(3H, t, J=7.0 Hz); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 172.8 (C), 148.3 (C),147.6 (C), 130.9 (C), 122.0 (C), 114.5 (C), 112.4 (CH), 109.4 (CH),102.0 (CH₂), 68.5 (CH), 61.4 (CH₂), 57.1 (CH), 44.3 (C), 41.4 (CH₂),23.3 (CH₃), 14.2 (CH₃). IR (film): ν/cm⁻¹ 3366, 2981, 2904, 2237, 1737,1504, 1477, 1408, 1241, 1205, 1117, 1037, 931, 846. LR-MS: 381.2 M+Na⁺.

Ethylrac-(2S,4S,5R)-5-(5-Bromo-2-methoxyphenyl)-4-cyano-4-methylpyrrolidine-2-carboxylate

Isolated as brown oil (single diastereomer). ¹H-NMR (500 MHz, CDCl₃):δ/ppm 7.89 (1H, d, J=2.5 Hz), 7.37 (1H, dd, J=2.5, 9.0 Hz), 6.77 (1H, d,J=9.0 Hz), 4.47 (1H, s), 4.27 (2H, q, J=7.5 Hz), 3.98 (1H, t, J=7.5 Hz),3.83 (3H, s), 2.71 (1H, br s), 2.62 (1H, dd, J=7.0, 13.0 Hz), 2.26 (1H,dd, J=8.5, 13.0 Hz), 1.49 (3H, s), 1.34 (3H, t, J=7.5 Hz); ¹³C-NMR (125MHz, CDCl₃): δ/ppm 172.7 (C), 156.4 (C), 131.9 (CH), 131.1 (CH), 129.1(C), 122.3 (C), 113.1 (C), 112.2 (CH), 64.5 (CH), 61.5 (CH₂), 57.7 (CH),55.5 (CH₃), 43.9 (C), 41.8 (CH₂), 23.6 (CH₃), 14.3 (CH₃). IR (film):ν/cm⁻¹ 3366, 2980, 2938, 2904, 2839, 2236, 1736, 1486, 1463, 1252, 1202,1134, 1028, 809. LR-MS: 389.0 M+Na⁺; HR-MS (ESI) calculated forC₁₆H₁₉N₂O₃Na: 389.0477, found: 389.0471.

Ethylrac-(2S,4S,5S)-4-Cyano-5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4-methylpyrrolidine-2-carboxylate

Isolated as yellow oil (dr=4:1). ¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.38(1H, s), 7.22 (1H, d, J=8.5 Hz), 7.06 (1H, d, J=8.5 Hz), 4.24-4.34 (2H,m), 3.97 (1H, s), 3.95-4.01 (1H, m), 2.84 (1H, dd, J=4.5, 9.0 Hz), 2.68(1H, s), 2.29 (1H, dd, J=4.5, 8.5 Hz), 1.44 (3H, s), 1.33 (3H, t, J=9.0Hz); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 172.7 (C), 144.1 (C), 133.7 (C),133.3 (C), 131.8 (C, t, J=250 Hz), 123.1 (CH), 121.6 (C), 109.3 (CH),109.1 (CH), 71.9 (CH), 61.8 (CH₂), 57.0 (CH), 43.9 (C), 41.8 (CH₂), 22.1(CH₃), 14.2 (CH₃). IR (film): ν/cm⁻¹ 3351, 3078, 2983, 2236, 1738, 1497,1448, 1382, 1239, 1148, 1034, 818, 703.

Ethylrac-(2S,4S,5S)-5-(3,4-Bis(allyloxy)phenyl)-4-cyano-4-methylpyrrolidine-2-carboxylate

Isolated as yellow oil (dr=4:1). ¹H-NMR (500 MHz, CDCl₃) δ/ppm 7.17 (d,J=1.5 Hz, 1H), 7.01-6.99 (m, 1H), 6.89 (d, J=8.2 Hz, 1H), 6.13-6.04 (m,2H), 5.47-5.40 (m, 2H), 5.31-5.26 (m, 2H), 4.66-4.60 (m, 4H), 4.33-4.26(m, 2H), 3.96 (dd, J=9.6, 3.9 Hz, 1H), 3.85 (s, 1H), 2.82 (dd, J=13.6,4.1 Hz, 1H), 2.75 (broad s, 1H), 2.27 (dd, J=13.6, 9.7 Hz, 1H), 1.40 (s,3H), 1.33 (t, J=7.6 Hz, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ/ppm 173.2(C), 149.1 (C), 148.6 (C), 133.5 (2×CH), 129.4 (C), 122.2 (C), 120.5(CH), 118.0 (CH₂), 117.8 (CH₂), 113.8 (CH), 113.4 (CH), 72.4 (CH), 70.2(CH₂), 70.0 (CH₂), 61.8 (CH₂), 57.3 (CH), 44.0 (C), 42.5 (CH₂), 22.1(CH₃), 14.3 (CH₃) ppm; IR (film) ν/cm⁻¹ 2982, 2936, 1735, 1649, 1513,1454, 1426, 1378, 1265, 1217, 1138, 1021, 997, 929, 810 cm⁻¹; HRMS (ESI)calcd for C₂₁H₂₆N₂O₄Na⁺ (M+Na) 393.1790, found 393.1796.

Ethylrac-(2S,4S,5S)-4-Cyano-5-(7-methoxybenzo[d][1,3]dioxol-5-yl)-4-methylpyrrolidine-2-carboxylate

Isolated as yellow oil (dr=3:2). ¹H-NMR (500 MHz, CDCl₃) δ/ppm 6.78 (s,1H), 6.67 (s, 1H), 5.96 (s, 2H), 4.29-4.22 (m, 2H), 3.93 (dd, J=9.5, 4.3Hz, 1H), 3.91 (s, 3H), 3.82 (s, 1H), 2.78 (dd, J=13.6, 4.3 Hz, 1H), 2.68(broad s, 1H), 2.24 (dd, J=13.6, 9.6 Hz, 1H), 1.40 (s, 3H), 1.31 (t,J=7.2 Hz, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ/ppm 172.9 (C), 148.8 (C),143.6 (C), 135.6 (C), 131.4 (C), 122.0 (C), 107.1 (CH), 101.9 (CH),101.7 (CH₂), 72.3 (CH), 61.7 (CH₂), 57.1 (CH₃), 56.7 (CH), 43.9 (C),42.1 (CH₂), 22.2 (CH₃), 14.2 (CH₃) ppm; IR (film) ν/cm⁻¹ 2979, 2235,1735, 1635, 1510, 1452, 1381, 1323, 1291, 1202, 1138, 1094, 1043, 929,855, 831, 733 cm⁻¹; HRMS (ESI) calcd for C₁₇H₂₀N₂O₅Na⁺ (M+Na) 355.1270,found 355.1261.

Ethylrac-(2S,4S,5S)-4-Cyano-5-(2,3-dihydro-1H-inden-5-yl)-4-methylpyrrolidine-2-carboxylate

Isolated as yellow oil (dr=1:1). ¹H-NMR (500 MHz, CDCl₃) δ 7.40 (s, 1H),7.27-7.23 (m, 2H), 4.34-4.26 (m, 2H), 3.98 (dd, J=9.6, 3.9 Hz, 1H), 3.90(s, 1H), 2.97-2.89 (m, 4H), 2.83 (dd, J=13.8, 4.2 Hz, 1H), 2.30 (dd,J=13.8, 9.7 Hz, 1H), 2.09 (app. quintet, J=7.4 Hz, 2H), 1.62 (broad s,1H), 1.42 (s, 3H), 1.35 (t, J=7.3 Hz, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃)δ 173.2 (C), 145.3 (C), 144.8 (C), 134.3 (C), 125.6 (CH), 124.5 (CH),123.4 (CH), 122.2 (C), 72.8 (CH), 61.8 (CH₂), 57.5 (CH), 44.2 (C), 42.8(CH₂), 33.0 (CH₂), 32.8 (CH₂), 25.6 (CH₂), 22.1 (CH₃), 14.4 (CH₃) ppm;IR (film) ν/cm⁻¹ 2940, 2234, 1735, 1447, 1378, 1209, 1139, 1097, 1032,826 cm⁻¹; HRMS (ESI) calcd for C₁₈H₂₂N₂O₂Na⁺ (M+Na) 321.1579, found321.1577.

Ethylrac-(2S,4S,5S)-4-Cyano-4-methyl-5-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrrolidine-2-carboxylate

Isolated as a yellow, highly viscous oil. ¹H-NMR (500 MHz, CDCl₃) δ 7.98(d, J=6.4 Hz, 2H), 7.93 (d, J=8.3 Hz, 2H), 7.59 (d, J=7.9 Hz, 1H), 7.52(t, J=7.4 Hz, 1H), 7.43 (t, J=7.8 Hz, 2H), 7.32 (t, J=7.7 Hz, 1H), 7.23(t, J=7.6 Hz, 1H), 4.35-4.28 (m, 2H), 4.27 (d, J=5.6 Hz, 1H), 4.04-4.00(m, 1H), 2.88 (dd, J=13.7, 4.3 Hz, 1H), 2.81 (broad s, 1H), 2.33 (dd,J=13.7, 9.8 Hz, 1H), 1.46 (s, 3H), 1.37 (t, J=7.1 Hz, 3H) ppm; ¹³C-NMR(126 MHz, CDCl₃) δ 172.7 (C), 137.9 (C), 135.1 (C), 134.0 (CH), 129.8(C), 129.4 (CH), 127.2 (CH), 125.2 (CH), 125.1 (CH), 123.4 (CH), 122.2(C), 119.8 (CH), 119.1 (C), 113.9 (CH), 64.6 (CH), 61.9 (CH₂), 57.4(CH), 44.6 (C), 42.6 (CH₂), 22.4 (CH₃), 14.3 (CH₃) ppm; IR (film) ν/cm⁻¹2980, 2235, 1735, 1606, 1447, 1369, 1273, 1212, 1176, 1125, 1092, 1024,979, 858, 750, 722 cm⁻¹; HRMS (ESI) calcd for C₂₃H₂₃N₃O₄SNa⁺ (M+Na)460.1307, found 460.1305.

Example 3 General Procedure for Forming Diketopiperazines by SequentialReaction of Pyrrolidine Esters with 2-Chloroalkanonyl Chlorides andAmines Methylrac-(3R,6S,7S,8aS)-6-(4-Fluorophenyl)-2,3,7-trimethyl-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-7-carboxylate

The corresponding pyrrolidine (1.0 equiv) was dissolved in 10 mL ofCH₂Cl₂ and cooled to 0° C. with an ice-bath. Triethylamine (1.2 equiv)was added, followed by dropwise addition of a solution of2-chloropropionyl chloride (1.2 equiv, 50% v/v in CH₂Cl₂). This mixturewas stirred for 1 h with cooling, followed by 1 h after removal of theice-bath. The intermediate α-chloroamide is then directly extracted (3×CH₂Cl₂) and isolated as brownish foam after removal of the volatiles invacuo. The corresponding amide was re-dissolved in 10 mL of CH₂Cl₂ andcombined with the equivalent volume of 40% aq MeNH₂ solution to give abiphasic mixture, which was stirred at rt for 12-16 h. Extraction ofthis mixture gives the crude diketopiperazine (DKP) product as yellowfoam (purity 50-80%). This residue was stirred with MeOH (1 M) for 1 h,whereupon a colorless solid was obtained ˜70% yield. Trituration of thismaterial from a methanolic solution in CH₂Cl₂ (often accelerated byvigorous stirring) gave the major DKP stereoisomer as a colorless solidafter filtration and drying under high vacuum. Either the pure DKPstereoisomer, or the solid 5:1 mixture of DKP isomers, could be employedin the subsequent sulfidation step.

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.00-7.10 (2H, m), 6.91 (2H, t, J=8.5Hz), 4.81 (1H, s), 4.36 (1H, dd, J=6.5, 11.5 Hz), 3.81 (1H, q, J=9.0Hz), 3.22 (3H, s), 2.94 (3H, s), 2.90-2.95 (1H, m), 2.16 (1H, dd, J=6.5,14.0 Hz), 1.53 (3H, s), 1.44 (3H, d, J=9.0 Hz); ¹³C-NMR (125 MHz,CDCl₃): δ/ppm 172.1 (C), 167.3 (C), 166.9 (C), 162.3 (C, d, J=249 Hz),133.6 (C, d, J=3 Hz), 128.3 (2 CH, d, J=8 Hz), 115.2 (2 CH, d, J=21 Hz),69.4 (CH), 60.9 (CH), 56.9 (CH), 53.3 (C), 51.9 (CH₃), 34.4 (CH₂), 32.0(CH₃), 24.2 (CH₃), 15.3 (CH₃). IR (film): ν/cm⁻¹ 2975, 2929, 1736, 1677,1605, 1509, 1433, 1401, 1299, 1248, 1225, 1126, 1158, 849. LR-MS: 371.07(M+Na⁺); HR-MS (ESI) calculated for C₁₈H₂₂N₂O₄F: 349.1564 (M+H⁺), found:349.1570.

tert-Butylrac-(3R,6S,7S,8aS)-6-(4-Fluorophenyl)-2,3,7-trimethyl-1,4-dioxooctahydropyr-rolo[1,2-a]pyrazine-7-carboxylate

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.06-7.13 (2H, m), 6.91-6.95 (2H, m),4.76 (1H, s), 4.34 (1H, dd, J=7.0, 12.0 Hz), 3.79 (1H, q, J=7.0 Hz),3.00 (3H, s), 2.92-3.00 (1H, m), 2.17 (1H, dd, J=6.5, 14.0 Hz), 1.51(3H, s), 1.45 (3H, d, J=7.0 Hz), 1.05 (9H, s); ¹³C-NMR (125 MHz, CDCl₃):δ/ppm 170.8 (C), 167.3 (C), 166.7 (C), 162.3 (C, d, J=250 Hz), 134.2(C), 129.2 (2CH), 115.1 (2CH, d, J=21 Hz), 81.4 (C), 69.3 (CH), 60.8(CH), 56.7 (CH), 53.4 (C), 34.8 (CH₂), 31.9 (CH₃), 27.3 (3CH₃), 25.2(CH₃), 15.2 (CH₃). IR (film): ν/cm⁻¹ 2977, 2934, 1724, 1673, 1510, 1452,1430, 1401, 1369, 1304, 1250, 1228, 1167, 1124, 848, 734. LR-MS: 413.2(M+Na⁺); HR-MS (ESI) calculated for C₂₁H₂₇N₂O₄FNa: 413.1852 (M+Na⁺),found: 413.1846.

Methylrac-(3R,6S,7S,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxooctahydropyrrolo-[1,2-a]pyrazine-7-carboxylate

Isolated as an 8:1 mixture of diastereomers, data for the major isomeris reported. ¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.68 (1H, d, J=8.0 Hz), 6.54(1H, d, J=8.0 Hz), 6.51 (1H, s), 5.90 (2H, s), 4.78 (1H), 4.36 (1H, dd,J=6.5, 11.5 Hz), 3.85 (1H, app. t, J=7.0 Hz), 3.32 (3H, s), 3.03 (3H,s), 2.90-3.00 (1H, m), 2.16 (1H, dd, J=6.5, 8.5 Hz), 1.53 (3H, s), 1.41(3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 172.09 (C), 167.2 (C), 166.8(C), 147.5 (C), 147.3 (C), 131.4 (C), 120.3 (CH), 108.0 (CH), 106.9(CH), 101.1 (CH₂), 69.8 (CH), 60.8 (CH), 56.8 (CH₃), 53.2 (C), 51.9(CH), 34.2 (CH₂), 32.0 (CH₃), 24.1 (CH₃), 15.2 (CH₃). LR-MS: 416.1M+Na⁺; IR (film): ν/cm⁻¹ 2953, 2949, 1735, 1672, 1490, 1432, 1294, 1245,1122, 1037. HR-MS (ESI) calculated for C₁₉H₂₂N₂O₆Na: 397.1375 (M+Na⁺),found: 397.1367.

Rac-(3R,6S,7S,8aS)-2,3,7-trimethyl-1,4-dioxo-6-phenyloctahydropyrrolo-[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (600 MHz, CDCl₃): δ/ppm 7.39-7.33 (3H, m), 7.12 (2H, d, J=7.2Hz), 4.91 (1H, s), 4.40 (1H, dd, J=6.6, 11.4 Hz), 3.91 (1H, q, J=3.6,7.2 Hz), 3.05 (3H, s), 2.79 (1H, t, J=11.4 Hz), 2.46 (1H, dd, J=6.6,13.2 Hz), 1.69 (3H, s), 1.48 (3H, d, J=7.2 Hz); ¹³C-NMR (125 MHz,CDCl₃): δ/ppm 166.7 (C), 166.2 (C), 136.9 (C), 129.2 (2CH), 129.1 (2CH),126.1 (CH), 119.9 (C), 69.8 (CH), 60.9 (CH), 56.3 (CH), 42.6 (C), 36.7(CH₂), 32.2 (CH₃), 25.3 (CH₃), 15.4 (CH₃); IR (film): ν/cm⁻¹ 2981, 2937,2244, 1673; LR-MS: 320.1 [M+Na]⁺; HR-MS (ESI) calculated forC₁₇H₁₉N₃O₂Na: 320.1375, found: 320.1380.

Rac-(3R,6S,7S,8aS)-6-(4-fluorophenyl)-2,3,7-trimethyl-1,4-dioxooctahydropyrrolo-[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.13-7.05 (4H, m), 4.90 (1H, s), 4.39(1H, dd, J=6.5, 11.0 Hz), 3.90 (1H, q, J=7.0 Hz), 3.06 (3H, s), 2.76(1H, t, J=12.0 Hz), 2.47 (1H, dd, J=6.5, 13.5 Hz), 1.69 (3H, s), 1.49(3H, d, J=7.5 Hz); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 166.8 (C), 166.1 (C),163.0 (C, d, J=247 Hz), 132.8 (C, d, J=3 Hz), 127.9 (2CH, d, J=8 Hz),119.8 (C), 116.2 (2CH, d, J=22 Hz), 69.2 (CH), 60.9 (CH), 56.3 (CH),42.6 (C), 36.8 (CH₂), 32.2 (CH₃), 25.3 (CH₃), 15.4 (CH₃); IR (film):ν/cm⁻¹ 2989, 2940, 2241, 1681; LR-MS: 338.1 [M+Na]⁺; HR-MS (ESI)calculated for C₁₇H₁₈FN₃O₂Na: 338.1281, found: 338.1283.

Rac-(3R,6S,7S,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxooctahydropyr-rolo[1,2-a]-pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.79 (1H, d, J=9.0 Hz), 6.63 (1H, d,J=9.0 Hz), 6.57 (1H, s), 5.96 (2H, s), 4.82 (1H, s), 4.36 (1H, dd,J=6.5, 11.0 Hz), 3.90 (1H, app q, J=7.0 Hz), 3.04 (3H, s), 2.76 (1H, appt, J=7.0 Hz), 2.45 (1H, dd, J=6.5, 13.5 Hz), 1.66 (3H, s), 1.47 (3H, d,J=7.0 Hz); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 166.6 (C), 166.0 (C), 148.2(C), 148.1 (C), 130.8 (C), 119.9 (CH), 119.8 (C), 108.6 (CH), 106.2(CH), 101.4 (CH₂), 69.6 (CH), 60.8 (CH), 56.1 (CH), 42.6 (C), 36.7(CH₂), 32.0 (CH₃), 25.1 (CH₃), 15.3 (CH₃). LR-MS: 364.0 M+Na⁺; IR (film)ν/cm⁻¹: 2982, 2917, 2244, 1671, 1491, 1447, 1246, 1037, 925, 721 ν/cm⁻¹.HR-MS (ESI) calculated for C₁₈H₁₉N₃O₄Na: 364.1273 (M+Na⁺), found:364.1273.

Rac-(6R,7S,8aS)-2,3,7-Trimethyl-1,4-dioxo-6-(thiophen-2-yl)octahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.31 (1H, m), 7.11 (1H, s), 7.06 (1H, m),5.27 (1H, s), 4.39 (1H, dd, J=6.5, 11.0 Hz), 3.95 (1H, q, J=7.5 Hz),3.08 (3H, s), 3.00 (1H, app t, J=13.0 Hz), 2.56 (1H, dd, J=6.5, 13.0Hz), 1.72 (3H, s), 1.52 (3H, d, J=7.5 Hz); ¹³C-NMR (125 MHz, CDCl₃):δ/ppm 166.9 (C), 166.0 (C), 140.4 (C), 127.5 (CH), 127.0 (CH), 125.5(CH), 119.6 (C), 65.3 (CH), 60.8 (CH), 55.8 (CH), 42.9 (C), 36.8 (CH₂),32.2 (CH₃), 24.5 (CH₃), 15.4 (CH₃). IR (film): ν/cm⁻¹ 2981, 2935, 2246,1672, 1447, 1428, 1402, 1301, 1229, 1065, 915, 722. LR-MS: 326.0 M+Na⁺.HR-MS (ESI) calculated for C₁₅H₁₇N₃O₂SNa: 326.0939 (M+Na⁺), found:326.0942.

Rac-(6S,7S,8aS)-6-(4-Chlorophenyl)-2,3,7-trimethyl-1,4-dioxooctahydropyrrol[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.35 (2H, d, J=8.5 Hz), 7.07 (2H, d,J=8.5 Hz), 4.88 (1H, s), 4.39 (1H, dd, J=6.5, 11.5 Hz), 3.90 (1H, q,J=7.5 Hz), 3.06 (3H, s), 2.76 (1H, app t, J=12.0 Hz), 2.48 (1H, dd,J=6.5, 8.5 Hz), 1.70 (3H, s), 1.49 (3H, d, J=7.5 Hz); ¹³C-NMR (125 MHz,CDCl₃): δ/ppm 166.7 (C), 166.0 (C), 135.4 (C), 135.1 (C), 129.4 (2CH),127.5 (2CH), 119.7 (C), 69.2 (CH), 60.9 (CH), 56.3 (CH), 42.4 (C), 36.8(CH₂), 32.2 (CH₃), 25.3 (CH₃), 15.4 (CH₃). IR (film): ν/cm⁻¹ 2981, 2919,2852, 2246, 1673, 1490, 1430, 1303, 1235, 1093, 731. LR-MS: 354.0 M+Na⁺.HR-MS (ESI) calculated for C₁₇H₁₈N₃O₂ClNa: 354.0985 (M+Na⁺), found:354.0981.

Rac-(3R,6S,7S,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-2-(3-(dimethylamino)propyl)-3,7-dimethyl-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

Isolated as an 8:1 mixture of diastereomers, data for the major isomeris reported. ¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.74 (1H, d, J=8.0 Hz), 6.56(1H, d, J=8.0 Hz), 6.52 (1H, s), 5.91 (2H, s), 4.80 (1H, s), 4.35 (1H,dd, J=6.5, 11.0 Hz), 4.02 (1H, q, J=7.5 Hz), 3.83 (1H, dt, J=7.5, 13.5Hz), 3.00 (1H, dt, J=7.5, 13.5 Hz), 2.74 (1H, app t, J=12.0 Hz), 2.40(1H, dd, J=6.5, 13.5 Hz), 2.20-2.30 (2H, m), 2.14 (6H, s), 1.70-1.80(2H, m), 1.62 (3H, s), 1.43 (3H, d, J=6.5 Hz); ¹³C-NMR (125 MHz, CDCl₃):δ/ppm 167.1 (C), 166.3 (C), 148.3 (C), 148.2 (C), 131.0 (C), 119.9 (C),119.7 (CH), 108.6 (CH), 106.3 (CH), 101.5 (CH₂), 69.4 (CH), 59.3 (CH),56.3 (CH₂), 56.2 (CH), 45.4 (2CH₃), 43.3 (C), 42.7 (CH₂), 36.6 (CH₂),25.9 (CH₂), 25.1 (CH₃), 16.0 (CH₃). IR (film): ν/cm⁻¹ 2979, 2943, 2822,2781, 2244, 1672, 1491, 1448, 1427, 1245, 1037, 929, 811, 735. LR-MS:435.3 M+Na⁺. HR-MS (ESI) calculated for C₂₂H₂₈N₄O₄Na: 435.2008 (M+Na⁺),found: 435.2015.

Rac-(3R,6R,7S,8aS)-6-(6-Bromobenzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxooctahydro-pyrrolo[1,2-a]pyrazine-7-carbonitrile

Isolated as a 3:1 mixture of diastereomers, data for the major isomer isreported. ¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.07 (1H, s), 6.34 (1H, s),5.98 (2H, s), 5.34 (1H, s), 4.36 (1H, dd, J=6.5, 12.0 Hz), 3.92 (1H, q,J=7.0 Hz), 3.04 (3H, s), 2.66 (1H, app t, J=13.0 Hz), 2.48 (1H, dd,J=6.5, 13.0 Hz), 1.74 (3H, s), 1.47 (3H, d, J=7.0 Hz); ¹³C-NMR (125 MHz,CDCl₃): δ/ppm 166.5 (C), 166.0 (C), 148.7 (C), 148.1 (C), 129.1 (C),119.7 (C), 115.0 (C), 113.5 (CH), 105.0 (CH), 102.3 (CH2), 68.2 (CH),60.8 (CH), 56.4 (CH), 42.2 (C), 37.4 (CH2), 31.8 (CH3), 24.9 (CH3), 15.5(CH3). IR (film): ν/cm⁻¹ 2982, 2246, 1675, 1503, 1478, 1429, 1402, 1307,1248, 1120, 1036, 928. LR-MS: 435.3 HR-MS (ESI) calculated forC₁₈H₁₈BrN₃O₄Na: 442.0378 (M+Na⁺), found: 442.0369.

Rac-(3R,6S,7S,8aS)-2,3,7-Trimethyl-1,4-dioxo-6-(p-tolyl)octahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.17 (2H, d, J=7.5 Hz), 7.01 (2H, d,J=7.5 Hz), 4.88 (1H, s), 4.38 (1H, dd, J=7.0, 11.0 Hz), 3.89 (1H, q,J=7.0 Hz), 3.04 (3H, s), 2.79 (1H, app t, J=12.5 Hz), 2.44 (1H, dd,J=6.5, 12.5 Hz), 2.32 (3H, s), 1.67 (3H, s), 1.47 (3H, d, J=7.0 Hz);¹³C-NMR (125 MHz, CDCl₃): δ/ppm 166.7 (C), 166.2 (C), 138.9 (C), 134.0(C), 129.8 (2CH), 125.9 (2CH), 120.0 (C), 69.6 (CH), 60.9 (CH), 56.2(CH), 42.6 (C), 36.7 (CH₂), 32.1 (CH₃), 25.2 (CH₃), 21.3 (CH₃), 15.4(CH₃). IR (film): ν/cm⁻¹ 3054, 2982, 2935, 2877, 2243, 1681, 1515, 1452,1430, 1402, 1306, 1246, 1230, 1063, 804, 734. LR-MS: 334.0 M+Na⁺. HR-MS(ESI) calculated for C₁₈H₂₁N₃O₂Na: 334.1531, found: 334.1536. Thestructure and relative configuration of this sample was confirmed bysingle-crystal X-ray analysis.

Rac-(3R,6S,7S,8aS)-6-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-2,3,7-trimethyl-1,4-dioxooctahydro-pyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, 1:1 d₄-MeOD/CDCl₃): δ/ppm 6.61 (1H, d, J=7.0 Hz), 6.38(2H, m), 4.59 (1H, s), 4.28 (1H, m), 4.00 (4H, m), 3.69 (1H, q, J=9.0Hz), 2.82 (3H, s), 2.48 (1H, app t, J=12.0 Hz), 2.23 (1H, dd, J=8.5,12.0 Hz), 1.45 (3H, s), 1.26 (3H, d, J=9.0 Hz); ¹³C-NMR (125 MHz,CDCl₃): δ/ppm 167.3 (C), 166.6 (C), 144.0 (C), 143.7 (C), 130.2 (C),120.0 (C), 119.1 (CH), 117.6 (CH), 114.9 (CH), 69.3 (CH), 64.3 (2CH₂),60.8 (CH), 56.1 (CH), 42.7 (C), 36.5 (CH₂), 31.9 (CH₃), 24.7 (CH₃), 14.9(CH₃). IR (film): ν/cm⁻¹ 3056.3, 2982.2, 2936.7, 2878.2, 2244.2, 1672.0,1509.0, 1450.8, 1432.5, 1307.3, 1287.9, 1067.0, 886.5. LR-MS: 378.1M+Na⁺. HR-MS (ESI) calculated for C₁₉H₂₁N₃O₄Na: 378.1430, found:378.1433.

Rac-(3R,6S,7S,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-3,7-dimethyl-2-(2-morpholinoethyl)-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, 1:1 d₄-MeOD/CDCl₃): δ/ppm 6.61 (1H, d, J=9.5 Hz), 6.49(1H, d, J=9.5 Hz), 6.36 (1H, s), 5.77 (2H, s), 4.67 (1H, s), 4.31 (1H,dd, J=6.5, 11.0 Hz), 3.88 (1H, q, J=9.0 Hz), 3.80 (1H, m), 3.44-3.50(4H, m), 2.88-2.95 (1H, m), 2.55 (1H, app t, J=6.5 Hz), 2.20-2.45 (7H,m), 1.49 (3H, s), 1.31 (3H, d, J=9.0 Hz); ¹³C-NMR (125 MHz, CDCl₃):δ/ppm 167.4 (C), 166.5 (C), 148.2 (C), 148.1 (C), 131.0 (C), 120.2 (CH),120.0 (C), 108.5 (CH), 105.8 (CH), 101.5 (CH₂), 69.4 (CH), 66.9 (2CH₂),59.7 (CH), 56.4 (CH₂), 56.1 (CH), 53.7 (2CH₂), 42.8 (C), 41.6 (CH₂),36.5 (CH₂), 24.8 (CH₃), 15.6 (CH₃). IR (film): ν/cm⁻¹ 2955.4, 2858.2,2812.5, 2243.7, 1672.0, 1491.0, 1448.4, 1426.9, 1295.8, 1245.8, 1115.3,1036.5, 922.1. LR-MS: 441.3 M+H⁺. HR-MS (ESI) calculated forC₂₃H₂₈N₄O₅Na: 463.1957, found 463.1946.

Rac-(3R,6S,7S,8aS)-6-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxooctahydro-pyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.07 (1H, d, J=8.0 Hz), 6.90 (1H, d,J=8.0 Hz), 6.83 (1H, s), 4.88 (1H, s), 4.36-4.43 (1H, dd, J=6.5, 11.5Hz), 3.92 (1H, q, J=7.0 Hz), 3.07 (3H, s), 2.76 (1H, app t, J=12.0 Hz),2.51 (1H, dd, J=6.5, 13.5 Hz), 1.71 (3H, s), 1.50 (3H, d, J=7.0 Hz);¹³C-NMR (125 MHz, CDCl₃): δ/ppm 166.8 (C), 165.9 (C), 144.2 (C), 144.1(C), 133.3 (C), 131.7 (CF₂, t, J=255 Hz), 121.9 (CH), 119.6 (C), 110.0(CH), 107.4 (CH), 69.4 (CH), 60.5 (CH), 56.3 (CH), 42.6 (C), 36.9 (CH₂),32.2 (CH₃), 25.3 (CH₃), 15.4 (CH₃). IR (film): ν/cm⁻¹ 2984, 2939, 2246,1674, 1500, 1452, 1429, 1403, 1241, 1150, 912, 732. LR-MS: 400.2(M+Na⁺); HR-MS (ESI) calculated for C₁₈H₁₇N₃O₄F₂Na: 400.1085, found:400.1092.

Rac-(3R,6S,7R,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-7-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dimethyl-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.73 (1H, d, J=9.0 Hz), 6.2-7.0 (2H, brs), 5.95 (2H, d, J=9.0 Hz), 5.35 (1H, s), 4.62 (1H, 1H, m), 3.88 (1H, q,J=7.5 Hz), 3.29 (1H, d, J=9.5 Hz), 3.21 (1H, d, J=9.5 Hz), 3.05 (3H, s),2.58-2.62 (1H, m), 2.26 (1H, app t, J=12.0 Hz), 1.52 (3H, d, J=7.5 Hz),0.88 (9H, s), 0.01 (3H, s), −0.02 (3H, s); ¹³C-NMR (125 MHz, CDCl₃):δ/ppm 166.4 (C), 166.2 (C), 148.0 (2C), 128.2 (C), 121.7 (C), 108.5(CH), 101.5 (CH₂), 66.6 (CH), 63.5 (CH₂), 61.1 (CH), 57.0 (CH), 49.2(C), 33.1 (CH₂), 32.1 (CH₃), 25.7 (3CH₃), 18.2 (C), 15.4 (CH₃), −5.6(2CH₃), 2 aromatic CH not seen. IR (film): ν/cm⁻¹ 2930, 2884, 2857,2240, 1678, 1490, 1448, 1402, 1245, 1105, 1039, 928, 840, 780, 732.LR-MS: 494.3 (M+Na⁺); HR-MS (ESI) calculated for C₂₄H₃₃N₃O₅SiNa:494.2087, found: 494.2068.

Rac-(3R,6S,7R,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-7-(methoxymethyl)-2,3-dimethyl-1,4-dioxo-octahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.78 (1H, d, J=8.0 Hz), 6.65 (1H, d,J=8.0 Hz), 6.59 (1H, s), 5.95 (2H, s), 5.03 (1H, s), 4.36 (1H, dd,J=7.0, 11.0 Hz), 3.88 (1H, q, J=7.0 Hz), 3.62 (2H, s), 3.48 (3H, s),3.02 (3H, s), 2.74 (1H, app t, J=11.5 Hz), 2.67 (1H, dd, J=7.5, 14.0Hz), 1.44 (3H, d, J=7.0 Hz); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 166.7 (C),166.2 (C), 148.3 (C), 148.2 (C), 130.8 (C), 120.0 (CH), 118.3 (C), 108.8(CH), 106.4 (CH), 101.5 (CH₂), 74.8 (CH₂), 65.4 (CH), 60.8 (CH), 59.8(CH₃), 56.8 (CH), 48.7 (C), 33.7 (CH₂), 32.1 (CH₃), 15.3 (CH₃).

Rac-(3R,6R,7S,8aS)-6-(Benzo[d][1,3]dioxol-4-yl)-2,3,7-trimethyl-1,4-dioxooctahydropyr-rolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, d₆-DMSO, 390K): δ/ppm 6.85 (2H, br s), 6.65 (1H, br s),6.00 (1H, s), 5.92 (1H, s), 4.96 (1H, s), 4.67 (1H, dd, J=6.5, 10.5 Hz),3.95 (1H, q, J=7.0 Hz), 2.97 (3H, s), 2.58-2.67 (1H, m), 2.44-2.55 (1H,m), 1.72 (3H, s), 1.46 (3H, d, J=7.0 Hz); ¹³C-NMR (125 MHz, d₆-DMSO,390K): δ/ppm 166.8 (C), 166.6 (C), 147.9 (C), 145.0 (C), 122.1 (CH),121.1 (C), 120.5 (CH), 108.7 (CH), 101.4 (CH₂), 65.6 (CH), 60.6 (CH),56.4 (CH), 42.7 (C), 38.1 (CH₂), 31.8 (CH₃), 25.0 (CH₃), 15.6 (CH₃). IR(film): ν/cm⁻¹ 3056, 2981, 2895, 2244, 1672, 1460, 1432, 1402, 1251,1066, 928, 731. LR-MS: 342.1 (M+H⁺); HR-MS (ESI) calculated forC₁₈H₁₉N₃O₄Na: 364.1273, found: 364.1267.

Rac-(3R,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2-butyl-3,7-dimethyl-1,4-dioxo-octahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.79 (1H, d, J=9.0 Hz), 6.60 (1H, d,J=9.0 Hz), 6.55 (1H, s), 5.96 (2H, s), 4.82 (1H, s), 4.38 (1H, dd,J=6.5, 11.0 Hz), 3.95 (1H, app q, J=7.0 Hz), 2.99 (1H, m), 2.81 (1H, appt, J=7.0 Hz), 2.43 (1H, dd, J=6.5, 13.5 Hz), 1.60 (2H, m), 1.56 (3H, s),1.45 (3H, d, J=7.0 Hz) 1.38 (2H, m), 0.96 (3H, t, J=7.2 Hz); ¹³C-NMR(125 MHz, CDCl₃): δ/ppm 167.2 (C), 166.3 (C), 148.6 (C), 148.4 (C),131.1 (C), 120.0 (CH), 119.9 (C), 108.8 (CH), 106.4 (CH), 101.7 (CH₂),69.7 (CH), 59.0 (CH), 56.5 (CH), 44.8 (C), 42.9 (CH₂), 36.9 (CH₂), 30.0(CH₂), 25.4 (CH₃), 20.2 (CH₂), 16.2 (CH₃). 13.9 (CH₃), LR-MS: 406.2M+Na⁺; IR (film): ν/cm⁻¹ 2982, 2917, 2244, 1671, 1491, 1447, 1246, 1037,925, 721 ν/cm⁻¹. HR-MS (ESI) calculated for C₂₁H₂₅N₃O₄Na: 406.1713(M+Na⁺), found: 406.1730.

Rac-(3R,6S,7S,8aS)-6-(4-methoxyphenyl)-2,3,7-trimethyl-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.05 (2H, d, J=8.5 Hz), 6.88 (2H, d,J=8.5 Hz), 4.88 (1H, s), 4.39 (1H, dd, J=6.5, 11.5 Hz), 3.90 (1H, q,J=7.5 Hz), 3.79 (3H, s), 3.05 (3H, s), 2.80 (1H, app t, J=12.0 Hz), 2.46(1H, dd, J=6.5, 8.5 Hz), 1.70 (3H, s), 1.48 (3H, d, J=7.5 Hz); ¹³C-NMR(125 MHz, CDCl₃): δ/ppm 166.6 (C), 166.2 (C), 159.9 (C), 128.9 (C),127.2 (2CH), 119.9 (C), 114.4 (2CH), 69.3 (CH), 60.9 (CH), 56.1 (CH),55.2 (CH3), 42.6 (C), 36.6 (CH₂), 32.1 (CH₃), 25.1 (CH₃), 15.3 (CH₃). IR(film): ν/cm⁻¹ 2981, 2919, 2852, 2246, 1673, 1490, 1303, 1235, 1093,756. HR-MS (ESI) calculated for C₁₈H₂₁N₃O₃Na: 350.1475 (M+Na⁺), found:350.1465.

Rac-(3R,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-3-ethyl-2,7-dimethyl-1,4-dioxo-octahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

Prepared from the corresponding pyrrolidine ester and 2-chlorobutanoylchloride by conducting the reaction with methylamine at 60° C.overnight. Isolated as a 9:1 mixture of diastereomers; NMR data for themajor isomer is reported. ¹H-NMR (600 MHz, CDCl₃) δ 6.79 (d, J=8.0 Hz,1H), 6.63 (dd, J=8.0, 1.9 Hz, 1H), 6.56 (t, J=1.9 Hz, 1H), 5.96 (s, 2H),4.83 (s, 1H), 4.41 (dd, J=8.0, 1.9 Hz, 1H), 3.77 (dd, J=7.5, 6.3 Hz,1H), 3.08 (s, 3H), 2.76 (dd, J=13.0, 11.7 Hz, 1H), 2.45 (dd, J=13.2, 6.7Hz, 1H), 1.95-1.92 (m, 1H), 1.91-1-85 (m, 1H), 1.66 (s, 3H), 1.07 (t,J=7.4 Hz, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ 166.4 (C), 166.2 (C),148.4 (C), 148.3 (C), 131.0 (C), 120.0 (CH), 119.9 (C), 108.8 (CH),106.3 (CH), 101.6 (CH₂), 69.9 (CH), 66.8 (CH), 56.3 (CH), 42.7 (C), 37.0(CH₂), 33.5 (CH₃), 25.4 (CH₃), 24.4 (CH₂), 10.6 (CH₃) ppm; IR (film)ν/cm⁻¹ 2929, 2245, 1672, 1491, 1446, 1402, 1246, 1038, 916, 821, 730cm⁻¹; HRMS (ESI) calcd for C₁₉H₂₁N₃O₄Na⁺ (M+Na) 378.1430, found378.1433.

Rac-(3R,6S,7S,8aS)-2-allyl-6-(benzo[d][1,3]dioxol-5-yl)-3,7-dimethyl-1,4-dioxo-octahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

The cyclization to the diketopiperazine was performed in a THF/H₂O (1:1)solvent mixture at 80° C., overnight. ¹H-NMR (600 MHz, CDCl₃) δ6.80-6.78 (m, 1H), 6.63-6.61 (m, 1H), 6.56 (d, J=1.6 Hz, 1H), 5.98-5.96(m, 2H), 5.81-5.74 (m, 1H), 5.27 (dd, J=10.2, 1.1 Hz, 1H), 5.24 (dd,J=17.0, 1.1 Hz, 1H), 4.84 (s, 1H), 4.50 (ddt, J=15.3, 5.3, 1.4 Hz, 1H),4.41 (dd, J=11.7, 6.7 Hz, 1H), 3.97 (q, J=7.4 Hz, 1H), 3.68 (dd, J=15.2,6.8 Hz, 1H), 2.82 (dd, J=13.3, 11.5 Hz, 1H), 2.46 (dd, J=13.3, 6.8 Hz,1H), 1.68 (s, 3H), 1.48 (d, J=7.4 Hz, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃)δ 167.0 (C), 166.1 (C), 148.4 (C), 148.3 (C), 131.8 (CH), 131.0 (C),119.9 (CH), 119.3 (CH₂), 108.8 (CH), 106.3 (CH), 101.6 (CH₂), 69.6 (CH),58.2 (CH), 56.3 (CH), 54.7 (C), 47.1 (CH₂), 42.8 (C), 36.7 (CH₂), 25.4(CH₃), 16.0 (CH₃) ppm; IR (film) ν/cm⁻¹ 2924, 2853, 2244, 1674, 1505,1448, 1427, 1294, 1246, 1184, 1101, 1038, 933, 859, 809, 735 cm⁻¹; HRMS(ESI) calcd for C₂₀H₂₁N₃O₄Na⁺ (M+Na) 390.1430, found 390.1438.

Rac-(3R,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2-cyclopropyl-3,7-dimethyl-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

Cyclization to the diketopiperazine was performed using cyclopropylamine(3.5 equiv) in a THF/H₂O (1:1) solvent mixture that was heated from80-100° C. over 2 d. ¹H-NMR (500 MHz, CDCl₃) δ 6.76 (d, J=8.0 Hz, 1H),6.56 (d, J=8.0 Hz, 1H), 6.47 (s, 1H), 5.95 (s, 2H), 4.80 (s, 1H), 4.38(dd, J=11.3, 6.7 Hz, 1H), 3.98 (q, J=7.3 Hz, 1H), 2.74-2.69 (m, 2H),2.45 (dd, J=13.3, 6.7 Hz, 1H), 1.65 (s, 3H), 1.49 (d, J=7.3 Hz, 3H),1.09 (dq, J=9.5, 6.6 Hz, 1H), 0.88-0.83 (m, 1H), 0.79 (dq, J=9.5, 6.5Hz, 1H), 0.58 (dq, J=10.4, 5.2 Hz, 1H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ168.2 (C), 167.2 (C), 148.3 (C), 148.2 (C), 130.9 (C), 119.9 (CH), 119.8(CH), 108.7 (CH), 106.1 (CH), 101.5 (CH₂), 69.4 (CH), 59.8 (CH), 56.7(CH), 42.7 (C), 36.7 (CH₂), 28.0 (CH), 25.2 (CH₃), 16.2 (CH₃), 8.7(CH₂), 5.7 (CH₂) ppm; IR (film) ν/cm⁻¹ 2984, 1675, 1490, 1424, 1376,1245, 1189, 1036, 932, 733 cm⁻¹; HRMS (ESI) calcd for C₂₀H₂₁N₃O₄Na⁺(M+Na) 390.1430, found 390.1433.

Rac-(3R,6S,7S,8aS)-6-(3,4-bis(allyloxy)phenyl)-2,3,7-trimethyl-1,4-dioxooctahydro-pyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃) δ 6.86 (d, J=8.2 Hz, 1H), 6.65-6.63 (m, 2H),6.09-6.01 (m, 2H), 5.39 (dd, J=17.2 Hz, 1.1 Hz, 1H), 5.37 (dd, J=17.3Hz, 1.2 Hz, 1H), 5.26 (app. dt, J=10.6, 0.2 Hz, 2H), 4.85 (s, 1H),4.60-4.57 (m, 4H), 4.37 (dd, J=11.3, 6.8 Hz, 1H), 3.91 (q, J=7.2 Hz,1H), 3.06 (s, 3H), 2.78 (app t, J=12.2 Hz, 1H), 2.44 (dd, J=13.3, 6.8Hz, 1H), 1.68 (s, 3H), 1.49 (d, J=7.2 Hz, 3H) ppm; ¹³C-NMR (126 MHz,CDCl₃) δ 166.8 (C), 166.3 (C), 149.2 (C), 148.7 (C), 133.4 (CH), 133.4(CH), 129.6 (C), 119.9 (C), 118.7 (CH), 117.9 (CH₂), 117.9 (CH₂), 113.9(CH), 112.4 (CH), 70.2 (CH₂), 69.9 (CH₂), 69.5 (CH), 61.1 (CH), 56.2(CH), 42.7 (C), 36.7 (CH₂), 32.3 (CH₃), 25.3 (CH₃), 15.4 (CH₃) ppm; IR(film) ν/cm⁻¹ 2983, 1672, 1515, 1451, 1426, 1306, 1259, 1224, 1206,1139, 1017, 996, 924, 806, 732 cm⁻¹; HRMS (ESI) calcd for C₂₃H₂₇N₃O₄Na⁺(M+Na) 432.1899, found 432.1888.

Rac-(3R,6S,7S,8aS)-6-(7-methoxybenzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

Isolated as an 8:1 mixture of diasteromers; NMR data for the majorisomer is reported. ¹H-NMR (500 MHz, CDCl₃) δ 6.34 (s, 1H), 6.24 (s,1H), 5.97 (s, 2H), 4.81 (s, 1H), 4.36 (dd, J=11.3, 6.6 Hz, 1H), 3.92 (q,J=7.3 Hz, 1H), 3.89 (s, 3H), 3.05 (s, 3H), 2.78 (app. t, J=12.4 Hz, 1H),2.46 (dd, J=13.3, 6.6 Hz, 1H), 1.68 (s, 3H), 1.49 (d, J=7.3 Hz, 3H) ppm;¹³C-NMR (126 MHz, CDCl₃) δ 166.9 (C), 166.2 (C), 149.5 (C), 143.8 (C),135.9 (C), 131.6 (C), 119.9 (C), 107.0 (CH), 102.0 (CH₂), 99.7 (CH),69.8 (CH), 61.0 (CH), 56.8 (CH₃), 56.3 (CH), 42.8 (C), 36.8 (CH₂), 32.3(CH₃), 25.4 (CH₃), 15.5 (CH₃) ppm; IR (film) ν/cm⁻¹ 2981, 1143, 1673,1512, 1452, 1433, 1402, 1324, 1240, 1199, 1135, 1093, 1043, 927, 735cm⁻¹; HRMS (ESI) calcd for C₁₉H₂₁N₃O₅Na⁺ (M+Na) 394.1379, found394.1371.

Rac-(3R,6S,7S,8aS)-6-(2,3-dihydro-1H-inden-5-yl)-2,3,7-trimethyl-1,4-dioxooctahydro-pyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃) D 7.19 (d, J=7.7 Hz, 1H), 6.96 (s, 1H), 6.93 (d,J=7.7 Hz, 1H), 4.89 (s, 1H), 4.38 (dd, J=11.6, 6.7 Hz, 1H), 3.91 (q,J=7.3 Hz, 1H), 3.07 (s, 3H), 2.90-2.80 (m, 5H), 2.45 (dd, J=13.3, 6.6Hz, 1H), 2.05 (app. quintett, J=7.5 Hz, 2H), 1.69 (s, 3H), 1.49 (d,J=7.3 Hz, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ 166.8 (C), 166.3 (C),145.5 (C), 145.2 (C), 134.8 (C), 125.0 (CH), 123.9 (CH), 122.1 (CH),120.1 (C), 70.1 (CH), 61.0 (CH), 56.3 (CH), 42.8 (C), 36.8 (CH₂), 33.0(CH₂), 32.8 (CH₂), 32.2 (CH₃), 25.4 (CH₃), 25.4 (CH₂), 15.5 (CH₂) ppm;IR (film) ν/cm⁻¹ 1940, 1673, 1431, 1402, 1306, 1239, 1062, 814, 733cm⁻¹; HRMS (ESI) calcd for C₂₀H₂₃N₃O₂Na⁺ (M+Na) 360.1688, found360.1684.

Rac(3R,6S,7S,8aS)-2,3,7-trimethyl-1,4-dioxo-6-(1-(phenylsulfonyl)-1H-indol-3-yl)octahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

Isolated as an 7:1 mixture of diasteromers; NMR data for the majorisomer is reported. ¹H-NMR (500 MHz, CDCl₃) δ 7.89 (d, J=8.2 Hz, 1H),7.77 (d, J=7.5 Hz, 2H), 7.51 (app. t, J=7.3 Hz, 1H), 7.46-7.39 (m, 4H),7.31 (app. t, J=7.3 Hz, 1H), 7.25 (app. t, J=7.3 Hz, 1H), 5.18 (s, 1H),4.40 (dd, J=12.4, 6.3 Hz, 1H), 3.92 (q, J=7.4 Hz, 1H), 3.09 (s, 3H),2.83 (app. t, J=11.9 Hz, 1H), 2.57 (dd, J=13.3, 6.3 Hz, 1H), 1.73 (s,3H), 1.49 (s, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ 166.7 (C), 166.0 (C),137.9 (C), 135.4 (C), 134.1 (CH), 129.5 (CH), 126.8 (CH), 125.6 (CH),124.1 (CH), 123.9 (CH), 119.9 (CH), 119.6 (C), 119.5 (C), 119.4 (C),114.1 (CH), 62.4 (CH), 60.9 (CH), 56.2 (CH), 42.2 (C), 38.1 (CH₂), 32.3(CH₃), 25.1 (CH₃), 15.7 (CH₃) ppm; IR (film) ν/cm⁻¹ 2982, 1675, 1448,1367, 1307, 1175, 1124, 1095, 977, 748, 725 cm⁻¹; HRMS (ESI) calcd forC₂₅H₂₄N₄O₄SNa⁺ (M+Na) 499.1416, found 499.1412.

Alternate Procedure for Forming Diketopiperazines From SubstitutedProlidine Esters and Protected α-Amino AcidsRac-(3R,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-3-benzyl-2,7-dimethyl-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-7-carbonitrile

To a solution of N-Boc-phenylalanine (263 mg, 1.00 mmol, 1.5 equiv) indry CH₂Cl₂ (2 mL) at 0° C. was added N,N-diisopropylethylamine (0.12 mL,0.66 mmol, 1 equiv) and BOPCl (253 mg, 1.00 mmol, 1.5 equiv) and thereaction was allowed to warm to room temperature over 1 h. Afterrecooling to 0° C. additional N,N-diisopropylethylamine (0.23 mL, 1.3mmol, 2 equiv) was added, followed by the dropwise addition of asolution of the corresponding pyrrolidine ester (200 mg, 0.66 mmol, 1equiv) in CH₂Cl₂ (1.3 mL). The reaction was allowed to warm to roomtemperature overnight, after which time TLC analysis showed fullconversion of the starting material. After an extractive work-up(CH₂C2/water), the crude product was filtered through a silica gel plugusing hexanes/ethyl acetate (1:1) as the eluent and the volatiles wereremoved in vacuo. The crude acylated pyrrolidine ester was dissolved indry CH₂Cl₂ (2.1 mL) and cooled to 0° C. Trifluoroacetic acid (0.8 mL)was added, the reaction allowed to warm to rt over 3 h, and thevolatiles were removed under reduced pressure. The resulting residue wasdissolved in a 4:1 mixture i-BuOH/toluene (18 mL) containingN,N-diisopropylethylamine (0.46 mL, 2.65 mmol, 4 equiv). The vial wassealed with a teflon cap and heated to 100° C. overnight. After anextractive work up (CH₂Cl₂/water) and concentration, two diastereomericDKPs were separated by silica gel chromatography (eluent: hexanes/EtOAc1:3).

NMR data for diastereomer A: ¹H-NMR (600 MHz, CDCl₃) δ 7.38-7.35 (m,3H), 7.26-7.25 (m, 2H), 7.00 (d, J=3.7 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H),6.63 (d, J=7.2 Hz, 1H), 6.55 (s, 1H), 5.92 (s, 2H), 4.71 (s, 1H), 4.29(app. q, J=4.2 Hz, 1H), 3.31 (dd, J=13.9, 4.6 Hz, 1H), 2.95 (dd, J=13.9,4.4 Hz, 1H), 2.64 (dd, J=11.9, 6.2 Hz, 1H), 2.44 (app. t, J=12.5 Hz,1H), 2.05 (dd, J=13.0, 6.3 Hz, 1H), 1.32 (s, 3H) ppm. NMR data fordiastereomer B: ¹H-NMR (600 MHz, CDCl₃) δ 7.37-7.34 (m, 2H), 7.32-7.29(m, 1H), 7.22-7.19 (m, 2H), 6.81 (d, J=8.0 Hz, 1H), 6.64 (dd, J=8.8, 1.7Hz, 1H), 6.60 (d, J=1.8 Hz, 1H), 6.00 (d, J=1.5 Hz, 1H), 5.99 (d, J=1.5Hz, 1H), 5.69 (broad s, 1H), 4.91 (s, 1H), 4.40 (dd, J=11.3, 6.9 Hz,1H), 4.32 (dd, J=10.2, 4.2 Hz, 1H), 3.51 (dd, J=14.7, 3.9 Hz, 1H), 2.79(dd, J=11.5, 4.1 Hz, 1H), 2.77 (dd, J=10.3, 4.4 Hz, 1H), 2.40 (dd,J=13.4, 6.8 Hz, 1H), 1.68 (s, 3H) ppm.

Both DKP products were individually methylated in a separate reactionvessel by the following procedure: To the intermediate DKP (91 mg, 0.23mmol, 1 equiv) in acetone (2.8 mL) was added K₂CO₃ (620 mg, 4.5 mmol, 20equiv) and MeI (1.4 mL, 23 mmol, 100 equiv) and the reaction was stirredfor 2 d at room temperature with the exclusion of light. After anextractive work up (CH₂C2/water), each diasteromeric DKP was obtained asamorphous solid.

Diastereomer A: ¹H-NMR (500 MHz, CDCl₃) δ 7.34-7.31 (m, 3H), 7.18-7.13(m, 2H), 6.77 (d, J=7.8 Hz, 1H), 6.59 (d, J=7.8 Hz, 1H), 6.51 (s, 1H),5.95 (s, 2H), 4.65 (s, 1H), 4.18 (t, J=4.1 Hz, 1H), 3.28 (dd, J=14.1,3.9 Hz, 1H), 3.14-3.10 (m, 4H), 2.40-2.39 (m, 2H), 2.04-2.01 (m, 1H),1.26 (s, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ 166.5 (C), 165.5 (C), 148.3(C), 148.2 (C), 135.4 (C), 131.1 (C), 129.9 (CH), 129.2 (CH), 128.1(CH), 120.0 (C), 119.9 (CH), 108.8 (CH), 106.1 (CH), 101.5 (CH₂), 69.5(CH), 66.4 (CH), 55.4 (CH), 42.3 (C), 36.8 (CH₂), 36.4 (CH₂), 32.4(CH₃), 24.8 (CH₃) ppm; IR (film) ν/cm⁻¹ 2934, 2247, 1673, 1505, 1491,1446, 1403, 1304, 1247, 1102, 1053 cm⁻¹; HRMS (ESI) calcd forC₂₄H₂₃N₃O₄Na⁺ (M+Na) 440.1586, found 440.1580. Diastereomer B: ¹H-NMR(500 MHz, CDCl₃) δ 7.26-7.19 (m, 3H), 7.14-7.11 (m, 2H), 6.76 (d, J=8.0Hz, 1H), 6.55 (d, J=8.4 Hz, 1H), 6.52 (s, 1H), 5.99-5.96 (m, 2H), 4.82(s, 1H), 4.43 (t, J=5.2 Hz, 1H), 4.37 (dd, J=11.3, 6.8 Hz, 1H), 3.48(dd, J=16.0, 5.6 Hz, 1H), 3.42 (dd, J=16.0, 5.5 Hz, 1H), 3.04 (s, 3H),2.81 (dd, J=13.1, 11.5 Hz, 1H), 2.46 (dd, J=13.4, 6.6 Hz, 1H), 1.66 (s,3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ 168.1 (C), 165.8 (C), 148.3 (2×C),136.5 (C), 130.8 (C), 129.0 (CH), 128.8 (CH), 127.1 (CH), 120.1 (C),120.0 (CH), 108.8 (CH), 106.7 (CH), 101.2 (CH₂), 69.8 (CH), 61.3 (CH),57.4 (CH), 42.8 (C), 37.0 (CH₂), 33.5 (CH₂), 30.9 (CH₃), 25.6 (CH₃) ppm;IR (film) ν/cm⁻¹ 1675, 1504, 1491, 1448, 1390, 1306, 1244, 1039, 912,733, 700 cm¹; HRMS (ESI) calcd for C₂₄H₂₃N₃O₄Na⁺ (M+Na) 440.1586, found440.1577.

Example 4 General Procedure for Synthesis of EpidithiodiketopiperazinesMethylRac-(3S,6S,7S,8aS)-6-(4-fluorophenyl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carboxylate

To a suspension of elemental sulfur (32 mg, 1.0 mmol) in dry THF (5 mL)was added a solution of NaHMDS (0.25 mL, 2 M in THF) at roomtemperature. After 1 min, a solution of the diketopiperazine (70 mg, 0.2mmol, in 2 mL THF) was added, followed by a second aliquot of NaHMDS(0.25 mL, 2 M in THF) within another 2 min. The resulting orange-brownsolution was stirred for 30 min at rt, cooled to 0° C. and quenched byaddition of aqueous NH₄Cl. After extractive work-up (CH₂Cl₂/water) andevaporation of the solvent, a yellow residue was obtained. This residuewas re-dissolved in a mixture of MeOH/THF (5 mL) to which NaBH₄ (350 mg,1 mmol) was added portionwise at 0° C. After stirring for 30 min, thismixture was quenched with aqueous NH₄Cl, extracted (CH₂Cl₂/water) andthe extract was dried over Na₂SO₄. After evaporation of the solvent, ayellow residue was obtained, which was subsequently dissolved in EtOAc(10 mL). A solution of KI₃ (0.5 M, 2 mL) in water was added and thebiphasic system was stirred at rt for 15 min, after which time 3 mL ofsaturated aqueous Na₂S₂O₃ was added to give a pale yellow EtOAc layer.Aqueous extraction and evaporation of the organic phase gives a yellowoil, which was purified by preparative TLC (Et₂O/CH₂Cl₂) to give thetitle compound as a yellow oil.

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.41 (2H, m), 7.03 (2H, t, J=9.0 Hz),5.09 (1H, s), 3.36 (3H, s), 3.34 (1H, d, J=14.5 Hz), 3.25 (1H, d, J=14.5Hz), 3.11 (3H, s), 1.97 (3H, s), 1.55 (3H, s); ¹³C-NMR (125 MHz, CDCl₃):δ/ppm 171.8 9 (C), 166.2 (C), 163.1 (C), 162.6 (C, d, J=250 Hz), 131.8(C), 129.4 (2CH, d, J=8 Hz), 115.5 (2CH, d, J=22 Hz), 74.6 (C), 73.4(C), 72.4 (CH), 55.1 (C), 52.3 (CH₃), 38.9 (CH₂), 27.8 (CH₃), 25.5(CH₃), 18.4 (CH₃). IR (film): ν/cm⁻¹ 2951, 1736, 1692, 1606, 1511, 1255,1228, 1161, 1129, 848, 733. LR-MS: 432.85 (M+Na⁺); HR-MS (ESI)calculated for C₁₈H₁₉N₂O₄FS₂Na: 433.0668, found: 433.0660.

Example 5 Alternate Simplified General Procedure for Synthesis ofEpidithiodiketopiperazinesRac-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-3-ethyl-2,7-dimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

To a suspension of S₈ (83 mg, 0.32 mmol) in dry THF (3.4 mL) was added asolution of NaHMDS (1.7 mL, 0.93 mmol, 3.3 equiv, 2 M in THF) at roomtemperature over 40 sec. After 1 min, a solution of the diketopiperazine(100 mg, 0.28 mmol, in 2.6 mL THF) was added dropwise, followed by asecond aliquot of NaHMDS (1.1 mL, 0.62 mmol, 2.2 equiv, 2 M in THF)within another 30-40 sec. The resulting orange-yellow solution wasstirred for 50 min at rt and quenched by addition of saturated aqueousNH₄Cl. After extractive work-up (CH₂Cl₂/water) and evaporation of thesolvent, a yellow-brown amorphous residue was obtained. This residue wasevaporated onto 2.2 g SiO₂ and placed on top of a filter frit containing12 g SiO₂. Washing of this SiO₂ plug with 150 mL of hexanes removes themajority of HMDS-related material. Subsequent washing with 150 mL ofMeCN elutes the sulfidated products as a mixture of epidi- andepitrisulfide products (epidi:epitri usually ˜9:1). These products wereseparated by preparative TLC (2-4% EtOAc/CH₂Cl₂). The desiredepidisulfide product (R_(f)˜0.3) was isolated as an off-white solid(purity ˜95%) after removal of the volatiles in vacuo.

¹H-NMR (600 MHz, CDCl₃) δ 6.88 (s, 1H), 6.84 (app. s, 2H), 5.99 (app. m,2H), 4.83 (s, 1H), 3.28 (d, J=15.0 Hz, 1H), 3.10 (s, 3H), 3.01 (d,J=15.0 Hz, 1H), 2.39 (m, 1H), 2.30 (m, 1H), 1.68 (s, 3H), 1.25 (t, J=7.2Hz, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ 166.6 (C), 161.0 (C), 148.6 (C),148.3 (C), 127.5 (C), 120.8 (CH), 120.4 (C), 108.6 (CH), 107.3 (CH),101.6 (CH₂), 78.0 (C), 73.5 (C), 72.6 (CH), 44.5 (C), 42.9 (CH₂), 28.8(CH₃), 25.4 (CH₂), 24.9 (CH₃), 9.9 (CH₃) ppm; IR (film) ν/cm⁻¹ 2917,1685, 1558, 1506, 1491, 1357, 1249, 1001, 928 cm⁻¹; HRMS (ESI) calcd forC₁₉H₁₉N₃O₄S₂Na⁺ (M+Na) 440.0715, found 440.0718.

At the end of the concentration process, MeOH (1-2 mL) and CH₂Cl₂ (1-2mL) can be added and then again removed in vacuo to facilitate theformation of a colorless powder. In other cases, the epidi- andepitrisulfide products can be separated by column chromatography onsilica gel using a mixtures of CH₂Cl₂ and EtOAc as the eluent. Generallyeither of the two procedures described above can be used to prepare theepidithiodiketopiperazine products.

tert-ButylRac-(3S,6S,7S,8aS)-6-(4-fluorophenyl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carboxylate

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.52-7.55 (2H, m), 7.09 (2H, t, J=8.5Hz), 5.04 (1H, s), 3.36 (1H, d, J=14.5 Hz), 3.31 (1H, d, J=14.5 Hz),3.14 (3H, s), 1.99 (3H, s), 1.56 (3H, s), 1.17 (9H, s); ¹³C-NMR (125MHz, CDCl₃): δ/ppm 170.4 (C), 166.3 (C), 163.0 (C), 161.7 (C, d, J=247Hz), 132.3 (C), 130.4 (2CH, d, J=8 Hz), 115.5 (2CH, d, J=22 Hz), 82.2(C), 74.4 (C), 73.5 (C), 72.2 (CH), 55.0 (C), 39.4 (CH₂), 27.8 (CH₃),27.5 (3CH₃), 26.6 (CH₃), 18.3 (CH₃). IR (film): ν/cm⁻¹ 2977, 2935, 1693,1511, 1367, 1310, 1229, 1132, 847. LR-MS: 475.1 (M+Na); HR-MS (ESI)calculated for C₂₁H₂₅N₂O₄FS₂Na: 475.1137, found: 475.1132.

MethylRac-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carboxylate

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.98 (1H, s), 6.87 (1H, d, J=8.0 Hz),6.76 (1H, d, J=8.0 Hz), 5.96 (2H, s), 5.03 (1H, s), 3.42 (3H, s), 3.34(1H, d, J=14.0 Hz), 3.22 (1H, d, J=14.0 Hz), 3.10 (3H, s), 1.96 (3H, s),1.52 (3H); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 171.6 (C), 166.3 (C), 163.1(C), 147.9 (C), 147.6 (C), 129.6 (C), 121.3 (CH), 108.2 (CH), 108.0(CH), 101.3 (CH₂), 74.6 (C), 73.4 (C), 72.9 (CH), 55.1 (C), 52.3 (CH₃),38.8 (CH₂), 27.8 (CH₃), 25.4 (CH₃), 18.4 (CH₃). IR (film): ν/cm⁻¹ 2953,1736, 1692, 1490, 1447, 1356, 1250, 1038. LR-MS: 459.2 M+Na⁺; HR-MS(ESI) calculated for C₁₉H₂₀N₂O₆S₂Na: 459.0660, found: 459.0652.

MethylRac-(3S,6S,7S,8aS)-6-(5-bromo-2-methoxyphenyl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carboxylate

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.54 (1H, s), 7.34 (1H, d, J=9.0 Hz),6.70 (1H, d, J=9.0 Hz), 5.52 (1H, s), 3.78 (3H, s), 3.33 (3H, s), 3.26(1H, d, J=14.5 Hz), 3.21 (1H, d, J=14.5 Hz), 3.09 (3H, s), 1.96 (3H, s),1.52 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 171.7 (C), 166.3 (C),162.8 (C), 155.5 (C), 132.1 (CH), 130.9 (CH), 126.9 (C), 113.2 (C),111.8 (CH), 74.8 (C), 73.3 (C), 67.2 (CH), 55.7 (CH₃), 54.4 (C), 52.2(CH₃), 40.6 (CH₂), 27.8 (CH₃), 25.0 (CH₃), 18.4 (CH₃). IR (film): ν/cm⁻¹2939, 1734, 1692, 1489, 1356, 1253, 1129, 1028, 914. LR-MS: 523.2(M+Na⁺); HR-MS (ESI) calculated for C₁₉H₂₁N₂O₅S₂BrNa: 522.9973 (M+Na⁺),found: 522.9972.

MethylRac-(3S,6S,7S,8aS)-2,3,7-trimethyl-1,4-dioxo-6-(pyridin-3-yl)hexahydro-6H-3,8a-epidithio-pyrrolo[1,2-a]pyrazine-7-carboxylate

Isolated as a 4:1 mixture of diastereomers, data for the major isomer isreported. ¹H-NMR (500 MHz, CDCl₃): δ/ppm 8.63 (1H, d, J=2.0 Hz), 8.54(1H, dd, J=2.0, 5.0 Hz), 7.81 (1H, d, J=8.0 Hz), 7.27-7.30 (1H, m), 5.10(1H, s), 3.36 3H, s), 3.25-3.34 (2H, m), 3.10 (3H, s), 1.96 (3H, s),1.57 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 171.4 (C), 166.2 (C),163.1 (C), 149.8 (CH), 149.2 (CH), 135.1 (CH), 131.8 (C), 123.5 (CH),74.6 (C), 73.4 (C), 70.5 (CH), 55.1 (C), 52.5 (CH₃), 39.1 (CH₂), 27.8(CH₃), 25.5 (CH₃), 18.3 (CH₃). IR (film): ν/cm⁻¹ 2927, 1735, 1690, 1354,1309, 1261, 1129, 916. LR-MS: 416.1 (M+Na⁺); HR-MS (ESI) calculated forC₁₇H₁₉N₃O₄S₂Na: 416.0715 (M+Na⁺), found: 416.0715.

Rac-(3S,6S,7S,8aS,9S)-2,3,7-trimethyl-1,4-dioxo-6-phenylhexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.46-7.38 (5H, m), 4.91 (1H, s), 3.32(1H, d, J=14.5 Hz), 3.09 (3H, s), 3.00 (1H, d, J=14.9 Hz), 1.94 (3H, s),1.69 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.7 (C), 162.2 (C),133.8 (C), 129.6 (CH), 129.1 (2CH), 126.9 (2CH), 120.2 (C), 73.4 (C),72.5 (CH), 44.5 (C), 43.0 (CH₂) 29.8 (C), 27.9 (CH₃), 24.9 (CH₃), 18.2(CH₃); IR (film): ν/cm⁻¹ 2917, 2849, 2361, 2341, 2241, 1705, 1680;LR-MS: 382.0 [M+Na]⁺; HR-MS (ESI) calculated for C₁₇H₁₇N₃O₂S₂Na:382.0660, found: 382.0671.

Rac(3S,6S,7S,8aS,9S)-6-(4-fluorophenyl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.37 (2H, dd, J=5.4, 8.4 Hz), 7.13 (2H,t, J=8.7 Hz), 4.89 (1H, s), 3.31 (1H, d, J=14.7 Hz), 3.08 (3H, s), 2.99(1H, d, J=15.0 Hz), 1.94 (3H, s), 1.68 (3H, s); ¹³C-NMR (125 MHz,CDCl₃): δ/ppm 165.6 (C), 163.4 (C, d, J=247 Hz), 162.2 (C), 129.6 (C, d,J=3 Hz), 128.8 (2CH, d, J=8 Hz), 120.2 (C), 116.2 (2CH, d, J=22 Hz),73.52 (C), 73.46 (C), 71.9 (CH), 44.5 (C), 42.9 (CH₂), 27.9 (CH₃), 24.7(CH₃), 18.2 (CH₃); IR (film): ν/cm⁻¹ 2991, 2356, 2239, 1706, 1682, 1512;LR-MS: 400.0 [M+Na]⁺; HR-MS (ESI) calculated for C₁₇H₁₆FN₃O₂S₂:400.0566, found: 400.0582.

Rac-(3S,6S,7S,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

Major ETP stereoisomer. ¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.96 (1H, s),6.91 (2H, app. s), 6.06 (2H, s), 4.89 (1H, s), 3.36 (1H, d, J=14.5 Hz),3.14 (3H, s), 3.06 (1H, d, J=14.5 Hz), 2.00 (3H, s), 1.73 (3H, s);¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.6 (C), 162.1 (C), 148.6 (C), 148.3(C), 127.5 (C), 120.7 (CH), 120.3 (C), 108.6 (CH), 107.2 (CH), 101.6(CH₂), 73.4 (C), 73.3 (C), 72.4 (CH), 44.4 (C), 42.8 (CH₂), 27.8 (CH₃),24.8 (CH₃), 18.1 (CH₃). IR (film): ν/cm⁻¹ 2984, 2902, 2250, 1688, 1491,1446, 1358, 1250, 1038, 731. LR-MS: 426.1 M+Na⁺; HR-MS (ESI) calculatedfor C₁₈H₁₇N₃O₄S2Na: 426.0558, found: 426.0555. The constitution andrelative configuration of this product was confirmed by single-crystalX-ray analysis.

Rac-(3R,6S,7S,8aR)-6-(Benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

Minor ETP stereoisomer. ¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.80 (1H, d,J=8.0 Hz), 6.60 (1H, d, J=8.0 Hz), 6.55 (1H, s), 5.99 (2H, s), 5.03 (1H,s), 3.80 (1H, d, J=15.0 Hz), 3.12 (3H, s), 2.51 (1H, d, J=15.0 Hz), 1.99(3H, s), 1.94 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.3 (C), 162.4(C), 148.6 (C), 148.5 (C), 129.4 (C), 120.1 (CH), 119.6 (C), 108.9 (CH),106.3 (CH), 101.6 (CH₂), 73.8 (C), 73.7 (C), 71.6 (CH), 43.8 (C), 42.3(CH₂), 27.9 (CH₃), 27.2 (CH₃), 18.3 (CH₃). IR (film): ν/cm⁻¹ 2988, 2940,2900, 2249, 1694, 1504, 1448, 1355, 1248, 1111, 1038, 912, 731. LR-MS:426.0 M+Na⁺; HR-MS (ESI) calculated for C₁₈H1₇N₃O₄S₂Na: 426.0558, found:426.0553.

Rac-(3S,6R,7S,8aS)-6-(5-Bromo-2-methoxyphenyl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.50 (1H, s), 7.45 (1H, dd, J=2.0, 8.5Hz), 6.83 (1H, d, J=8.5 Hz), 5.49 (1H, s), 3.90 (3H, s), 3.45 (1H, d,J=14.5 Hz), 3.10 (3H, s), 2.91 (1H, d, J=14.5 Hz), 1.98 (3H, s), 1.65(3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.7 (C), 162.7 (C), 155.8(C), 133.2 (CH), 129.9 (CH), 120.0 (C), 113.4 (C), 112.5 (CH), 73.7 (C),73.3 (C), 65.5 (CH), 55.6 (CH₃), 43.5 (C), 41.9 (CH₂), 27.9 (CH₃), 25.7(CH₃), 18.3 (CH₃). IR (film): ν/cm⁻¹ 2937, 2359, 1692, 1488, 1359, 1252,729. LR-MS: 490.0 (M+Na); HR-MS (ESI) calculated for C₁₈H₁₈N₃O₃BrS₂Na:489.9871, found: 489.9862.

Rac-(3S,6R,7S,8aS)-2,3,7-Trimethyl-1,4-dioxo-6-(thiophen-2-yl)hexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.36 (1H, d, J=4.5 Hz), 7.30 (1H, br. s),7.07 (1H, t, J=4.5 Hz), 5.30 (1H, s), 3.43 (1H, d, J=14.5 Hz), 3.00-3.15(4H, m), 1.96 (3H, s), 1.66 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm165.5 (C), 162.2 (C), 136.2 (C), 127.7 (CH), 127.6 (CH), 126.8 (CH),119.6 (C), 73.4 (C), 72.9 (C), 67.3 (CH), 44.3 (C), 42.0 (CH₂), 27.9(CH₃), 25.2 (CH₃), 18.2 (CH₃). IR (film): ν/cm⁻¹ 2917, 2361, 1699, 1403,1360, 1251, 1068, 848. LR-MS: 388.1 (M+Na⁺); HR-MS (ESI) calculated forC₁₅H₁₅N₃O₂S₃Na: 388.0224, found: 388.0221.

Rac-(3S,6S,7S,8aS)-6-([1,1′-Biphenyl]-4-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.72 (2H, d, J=8.5 Hz), 7.66 (2H, d,J=8.5 Hz), 7.45-7.53 (4H, m), 7.41 (1H, t, J=7.5 Hz), 5.02 (1H, s), 3.41(1H, d, J=15.0 Hz), 3.16 (3H, s), 3.09 (1H, d, J=15.0 Hz), 2.02 (3H, s),1.78 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.6 (C), 162.2 (C),142.3 (C), 140.4 (C), 132.6 (C), 128.8 (2CH), 127.7 (2CH), 127.6 (2CH),127.2 (CH+2CH), 120.2 (C), 73.5 (C), 73.4 (C), 72.2 (CH), 44.4 (C), 42.9(CH₂), 27.8 (CH₃), 24.8 (CH₃), 18.1 (CH₃). IR (film): ν/cm⁻¹ 2935, 2250,1689, 1488, 1448, 1414, 1358, 1252, 910. LR-MS: 458.2 (M+Na⁺); HR-MS(ESI) calculated for C₂₃H₂₁N₃O₂S₂Na: 458.0973, found: 458.0972.

Rac-(3S,6S,7S,8aS)-2,3,7-Trimethyl-1,4-dioxo-6-(p-tolyl)hexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.28-7.35 (4H, m), 4.94 (1H, s), 3.37(1H, d, J=15.0 Hz), 3.14 (3H, s), 3.06 (1H, d, J=15.0 Hz), 2.43 (3H, s),2.00 (3H, s), 1.74 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.7 (C),162.1 (C), 139.3 (C), 130.7 (C), 129.7 (2CH), 126.7 (2CH), 120.3 (C),73.5 (C), 73.3 (C), 72.4 (CH), 44.5 (C), 42.9 (CH₂), 27.8 (CH₃), 24.7(CH₃), 21.4 (CH₃), 18.1 (CH₃). IR (film): ν/cm⁻¹ 2990, 2921, 2245, 1685,1516, 1358, 1253, 816. LR-MS: 396.2 (M+Na⁺); HR-MS (ESI) calculated forC₁₈H₁₉N₃O₂S₂Na: 396.0816, found: 396.0800. The constitution and relativeconfiguration of this product was confirmed by single-crystal X-rayanalysis.

Rac-(3S,6S,7S,8aS)-6-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.90-7.00 (3H, m), 4.88 (1H, s), 4.32(4H, m), 3.36 (1H, d, J=14.5 Hz), 3.14 (3H, s), 3.05 (1H, d, J=14.5 Hz),2.00 (3H, s), 1.72 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.7 (C),162.2 (C), 144.4 (C), 143.7 (C), 126.9 (C), 120.2 (C), 119.9 (CH), 117.9(CH), 115.9 (CH), 73.4 (C), 73.3 (C), 72.0 (CH), 64.3 (2CH₂), 44.4 (C),42.7 (CH₂), 27.8 (CH₃), 24.9 (CH₃), 18.1 (CH₃). IR (film): ν/cm⁻¹ 2984,2938, 2251, 1690, 1592, 1509, 1360, 1288, 1260, 1067, 912. LR-MS: 439.9(M+Na⁺); HR-MS (ESI) calculated for C₁₉H₁₉N₃O₄S₂Na: 440.0715, found:440.0728.

Rac-(3S,6S,7S,8aS)-6-(4-Chlorophenyl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.42 (2H, d, J=8.5 Hz), 7.32 (2H, d,J=8.5 Hz), 4.87 (1H, s), 3.32 (1H, d, J=15.0 Hz), 3.08 (3H, s), 2.99(1H, d, J=15.0 Hz), 1.94 (3H, s), 1.68 (3H, s); ¹³C-NMR (125 MHz,CDCl₃): δ/ppm 165.5 (C), 162.1 (C), 135.5 (C), 132.2 (C), 129.3 (2CH),128.2 (2CH), 120.0 (C), 73.5 (C), 73.4 (C), 71.8 (CH), 44.3 (C), 42.9(CH₂), 27.8 (CH₃), 24.7 (CH₃), 18.1 (CH₃). IR (film): ν/cm⁻¹ 2992, 2941,2246, 1690, 1493, 1359, 1255, 1090, 825. LR-MS: 416.2 (M+Na⁺); HR-MS(ESI) calculated for C₁₇H₁₆N₃O₂ClS₂Na: 416.0270, found: 416.0261.

Rac-(3S,6S,7S,8aS)-6-(3,4-Dichlorophenyl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.53 (1H, d, J=8.0 Hz), 7.46 (1H, s),7.25 (1H, d, J=8.0 Hz), 4.85 (1H, s), 3.33 (1H, d, J=15.0 Hz), 3.09 (3H,s), 3.00 (1H, d, J=15.0 Hz), 1.95 (3H, s), 1.70 (3H, s); ¹³C-NMR (125MHz, CDCl₃): δ/ppm 165.4 (C), 162.0 (C), 133.9 (2C), 133.2 (C), 131.2(CH), 129.0 (CH), 126.2 (CH), 119.8 (C), 73.4 (2C), 71.2 (CH), 44.2 (C),42.9 (CH₂), 27.9 (CH₃), 24.8 (CH₃), 18.1 (CH₃). IR (film): ν/cm⁻¹ 2936,2250, 1696, 1472, 1359, 1252, 1136, 1031, 912, 730. LR-MS: 449.9(M+Na⁺); HR-MS (ESI) calculated for C₁₇H₁₅N₃O₂Cl₂S₂Na: 449.9880, found:449.9853.

Rac-(3S,6R,7S,8aS)-6-(6-Bromobenzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.07 (1H, s), 7.05 (1H, s), 6.02 (2H, s),5.22 (1H, s), 3.41 (1H, d, J=15.0 Hz), 3.08 (3H, s), 2.98 (1H, d, J=15.0Hz), 1.95 (3H, s), 1.75 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.5(C), 162.2 (C), 149.1 (C), 148.3 (C), 126.8 (C), 120.0 (C), 114.4 (C),113.2 (CH), 108.0 (CH), 102.3 (CH₂), 73.6 (C), 73.3 (C), 71.0 (CH), 44.2(C), 42.8 (CH₂), 27.8 (CH₃), 25.5 (CH₃), 18.1 (CH₃). IR (film): ν/cm⁻¹3043, 2986, 2913, 2243, 1694, 1504, 1480, 1355, 1242, 1118, 1037, 931,734. LR-MS: 504.1 (M+Na⁺); HR-MS (ESI) calculated for C₁₈H₁₆N₃O₄BrS₂Na:503.9663, found: 503.9647.

Rac-(3S,6S,7R,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-7-((dimethylamino)methyl)-2,3,7-trimethyl-tetrahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-1,4-dione

Prepared fromrac-(3R,6S,7S,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxo-octahydropyrrolo[1,2-a]-pyrazine-7-carbonitrileby conventional NiCl₂/NaBH₄ reduction of the nitrile, Eschweiler-Clarkedimethylation of the resulting primary amine and sulfidation.

H-NMR (500 MHz, CDCl₃): δ/ppm 6.91 (1H, s), 6.76-6.83 (2H, m), 5.97 (2H,s), 4.77 (1H, s), 3.18 (1H, d, J=14.5 Hz), 3.07 (3H, s), 2.55 (1H, d,J=14.5 Hz), 2.15 (6H, s), 1.97 (2H, s), 1.94 (3H, s), 1.27 (3H, s);¹³C-NMR (125 MHz, CDCl₃): δ/ppm 166.6 (C), 163.1 (C), 148.0 (C), 147.3(C), 130.0 (C), 121.3 (CH), 108.4 (CH), 108.1 (CH), 101.3 (CH₂), 74.9(C), 74.2 (CH), 73.5 (C), 66.1 (CH₂), 8.2 (2CH₃), 47.8 (C), 41.8 (CH₂),27.7 (CH₃), 26.5 (CH₃), 18.4 (CH₃). IR (film): ν/cm⁻¹ 2940, 2821, 2770,1690, 1490, 1445, 1379, 1353, 1249, 1104, 1038, 932, 734. LR-MS: 458.2(M+Na⁺); HR-MS (ESI) calculated for C₂₀H₂₅N₃O₄S₂Na: 458.1184, found:458.1185.

Rac-(3S,6R,7S,8aS)-6-(4-Methoxybenzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.52-6.62 (2H, m), 6.01 (2H, s), 4.84(1H, s), 3.89 (3H, s), 3.31 (1H, d, J=15.0 Hz), 3.09 (3H, s), 3.01 (1H,d, J=15.0 Hz), 1.96 (3H, s), 1.68 (3H, s); ¹³C-NMR (125 MHz, CDCl₃):δ/ppm 165.5 (C), 162.0 (C), 149.2 (C), 143.8 (C), 136.0 (C), 128.1 (C),120.2 (C), 106.1 (CH), 102.1 (CH₂), 101.2 (CH), 73.6 (C), 73.5 (C), 72.4(CH), 56.6 (CH₃), 44.5 (C), 42.7 (CH₂), 27.9 (CH₃), 25.1 (CH₃), 18.2(CH₃). IR (film): ν/cm⁻¹ 2940, 2902, 2241, 1696, 1636, 1513, 1453, 1358,1250, 1201, 1130, 1093, 1044, 874, 734. LR-MS: 456.0 M+Na⁺; HR-MS (ESI)calculated for C₁₉H₁₉N₃O₅S₂Na: 456.0664, found: 456.0653.

Rac-(3S,6S,7R,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-7-(methoxymethyl)-2,3-dimethyl-1,4-dioxohexa-hydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.91 (1H, s), 6.80-6.88 (2H, m), 5.99(2H, s), 5.26 (1H, s), 3.61 (1H, d, J=9.5 Hz), 3.58 (1H, d, J=15.0 Hz),3.54 (1H, d, J=9.5 Hz), 3.47 (3H, s), 3.08 (3H, s), 2.88 (1H, d, J=15.0Hz), 1.94 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.5 (C), 162.0 (C),148.4 (C), 148.3 (C), 128.0 (C), 120.9 (CH), 118.4 (C), 108.7 (CH),107.4 (CH), 101.5 (CH₂), 73.8 (C), 73.5 (C), 73.0 (CH₂), 67.2 (CH), 59.7(CH₃), 49.6 (C), 38.5 (CH₂), 27.8 (CH₃), 18.1 (CH₃). IR (film): ν/cm⁻¹2993, 2928, 2898, 2250, 1693, 1497, 1491, 1447, 1358, 1250, 1118, 1038,914, 731. LR-MS: 456.0 M+Na⁺; HR-MS (ESI) calculated for C₁₉H₁₉N₃O₅S₂Na:456.0664, found: 456.0650.

Rac-(3S,6S,7S,8aS)-6-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.09-7.15 (3H, m), 4.89 (1H, s), 3.33(1H, d, J=14.5 Hz), 3.08 (3H, s), 3.00 (1H, d, J=14.5 Hz), 1.95 (3H, s),1.69 (3H, s); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.4 (C), 162.1 (C),144.4 (C), 144.2 (C), 131.7 (C, t, J=255 Hz), 130.0 (C), 122.6 (CH),119.9 (C), 109.8 (CH), 108.3 (CH), 77.3 (C), 73.4 (C), 72.0 (CH), 44.4(C), 42.9 (CH₂), 27.9 (CH₃), 24.8 (CH₃), 18.1 (CH₃). IR (film): ν/cm⁻¹2986, 2942, 2253, 1697, 1501, 1450, 1358, 1240, 1154, 1034, 903, 731.LR-MS: 462.0 M+Na⁺; HR-MS (ESI) calculated for C₁₈H₁₅N₃O₄F₂S₂Na:462.0370, found: 462.0377.

Rac-(3R,6R,7S,8aR)-6-(5-Bromobenzo[d][1,3]dioxol-4-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.13 (1H, d, J=8.5 Hz), 6.69 (1H, d,J=8.5 Hz), 5.90 (1H, s), 5.80 (1H, s), 5.65 (1H, s), 3.88 (1H, d, J=15.5Hz), 3.06 (3H, s), 2.57 (1H, d, J=15.5 Hz), 2.12 (3H, s), 1.95 (3H, s);¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.5 (C), 161.6 (C), 147.6 (C), 145.1(C), 126.4 (CH), 119.6 (C), 117.7 (C), 114.9 (C), 110.5 (CH), 102.1(CH₂), 74.6 (C), 73.7 (C), 68.5 (CH), 44.3 (CH₂), 43.1 (C), 27.6 (CH₃),27.5 (CH₃), 18.3 (CH₃). IR (film): ν/cm⁻¹ 2986, 2880, 2250, 1695, 1457,1357, 1242, 1059, 1035, 932, 731. LR-MS: 503.9 M+Na⁺; HR-MS (ESI)calculated for C₁₈H₁₆N₃O₄S₂BrNa: 503.9663, found: 503.9655. Theconstitution and relative configuration of this product was confirmed bysingle-crystal X-ray analysis.

Rac-(3S,6R,7S,8aS)-6-(Benzo[d][1,3]dioxol-4-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.80-6.96 (3H, m), 6.02 (1H, s), 6.00(1H, s), 5.22 (1H, s), 3.35 (1H, d, J=15.0 Hz), 3.08 (3H, s), 2.98 (1H,d, J=15.0 Hz), 1.95 (3H, s), 1.70 (3H, s); ¹³C-NMR (125 MHz, CDCl₃):δ/ppm 165.6 (C), 162.2 (C), 147.6 (C), 145.2 (C), 122.3 (CH), 120.1 (C),119.5 (CH), 115.7 (C), 109.5 (CH), 101.3 (CH₂), 73.6 (C), 73.3 (C), 66.2(CH), 44.1 (C), 42.7 (CH₂), 27.8 (CH₃), 25.1 (CH₃), 18.2 (CH₃). IR(film): ν/cm⁻¹ 2991, 2905, 2241, 1697, 1462, 1357, 1249, 1063, 1029,931, 731. LR-MS: 426.0 M+Na⁺; HR-MS (ESI) calculated for C₁₈H₁₇N₃O₄S₂Na:426.0558, found: 426.0552. The constitution and relative configurationof this product was confirmed by single-crystal X-ray analysis.

Rac-(3S,6S,7R,8aS)-6-(Benzo[d][1,3]dioxol-5-yl)-2,3-dimethyl-7-(morpholinomethyl)-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.96 (1H, s), 6.91 (1H, d, J=8.0 Hz),6.84 (1H, d, J=7.0 Hz), 5.99 (2H, s), 5.17 (1H, s), 3.65-3.74 (4H, m),3.56 (1H, d, J=14.5 Hz), 3.04 (3H, s), 2.92 (1H, d, J=14.5 Hz),2.70-2.80 (2H, m), 2.60-2.75 (4H, m), 1.94 (3H, s); ¹³C-NMR (125 MHz,CDCl₃): δ/ppm 165.6 (C), 162.2 (C), 148.4 (C), 148.3 (C), 128.2 (C),121.1 (CH), 119.7 (C), 108.7 (CH), 107.6 (CH), 101.5 (CH₂), 73.7 (C),73.5 (C), 68.7 (CH), 67.1 (2CH₂), 63.4 (CH₂), 55.3 (2CH₂), 49.6 (C),39.5 (CH₂), 27.9 (CH₃), 18.2 (CH₃). IR (film): ν/cm⁻¹ 2958, 2855, 2816,2248, 1688, 1491, 1447, 1356, 1260, 1116, 1037, 914, 864, 730. LR-MS:511.1 M+Na⁺; HR-MS (ESI) calculated for C₂₂H₂₄N₄O₅S₂Na: 511.1086, found:511.1068.

Rac-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2-butyl-3,7-dimethyl-1,4-dioxohexahydro-1H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 6.88 (1H, s), 6.82 (2H, app. s), 5.99(2H, s), 4.81 (1H, s), 3.78, (1H, m), 3.30 (1H, d, J=14.5 Hz), 2.99 (1H,d, J=14.5 Hz), 1.98 (3H, s), 1.66 (3H, s), 1.62 (2H, m), 1.38 (2H, m),0.96 (3H, t, J=7.2 Hz); ¹³C-NMR (125 MHz, CDCl₃): δ/ppm 165.2 (C), 162.4(C), 148.7 (C), 148.4 (C), 127.7 (C), 120.8 (CH), 120.5 (C), 108.7 (CH),107.4 (CH), 101.7 (CH₂), 73.8 (C), 73.0 (C), 72.5 (CH), 44.6 (C), 43.3(CH₂), 43.0 (CH₂), 29.9 (CH₂), 25.0 (CH₃), 24.8 (CH₂), 20.4 (CH₂), 17.8(CH₃), 14.0 (CH₃). IR (film): ν/cm⁻¹ 2984, 2902, 2250, 1688, 1491, 1446,1358, 1250, 1038, 731. HR-MS (ESI) calculated for C₂₁H₂₃N₃O₄S₂Na:468.1022, found: 468.1018.

Rac-(3S,6S,7S,8aS)-6-(4-methoxyphenyl)-2,3,7-trimethyl-1,4-dioxohexahydro-1H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃): δ/ppm 7.30 (2H, d, J=8.5 Hz), 6.96 (2H, d,J=8.5 Hz), 4.85 (1H, s), 3.79 (3H, s), 3.28 (1H, d, J=15.0 Hz), 3.08(3H, s), 2.99 (1H, d, J=15.0 Hz), 1.94 (3H, s), 1.66 (3H, s); ¹³C-NMR(125 MHz, CDCl₃): δ/ppm 165.0 (C), 162.3 (C), 159.9 (C), 128.7 (C),127.3 (2CH), 117.8 (C), 114.7 (2CH), 73.6 (C), 73.4 (C), 72.0 (CH), 55.2(CH3), 44.2 (C), 42.7 (CH₂), 27.7 (CH₃), 24.8 (CH₃), 18.0 (CH₃). IR(film): ν/cm⁻¹ 2988, 2940, 2246, 1690, 1493, 1359, 1255, 1093, 756.HR-MS (ESI) calculated for C₁₈H₁₉N₃O₃S₂Na: 412.0760, found: 412.0753.

Rac-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-3-benzyl-2,7-dimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃) δ 7.33-7.31 (m, 2H), 7.29-7.24 (m, 3H), 6.86 (s,1H), 6.82-6.81 (m, 2H), 5.99-5.98 (m, 2H), 4.90 (s, 1H), 3.82 (d, J=15.3Hz, 1H), 3.75 (d, J=15.3 Hz, 1H), 3.32 (d, J=14.9 Hz, 1H), 3.07 (s, 3H),3.02 (d, J=14.9 Hz, 1H), 1.70 (s, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ166.4 (C), 161.4 (C), 148.6 (C), 148.3 (C), 133.6 (C), 129.9 (CH), 128.7(CH), 127.8 (CH), 127.4 (C), 120.8 (CH), 120.3 (C), 108.7 (CH), 107.4(CH), 101.6 (CH₂), 77.8 (C), 73.5 (C), 72.7 (CH), 44.5 (C), 42.9 (CH₂),36.6 (CH₂), 29.4 (CH₃), 25.0 (CH₃) ppm; IR (film) ν/cm⁻¹ 2917, 1695,1491, 1447, 1357, 1249, 1190, 1037, 931, 817 cm⁻¹; HRMS (ESI) calcd forC₂₄H₂₁N₃O₄S₂Na⁺ (M+Na) 502.0871, found 502.0867.

Rac-(3S,6S,7S,8aS)-2-allyl-6-(benzo[d][1,3]dioxol-5-yl)-3,7-dimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃) δ 6.88 (s, 1H), 6.84 (app. s, 2H), 5.99 (s, 2H),5.89-5.82 (m, 1H), 5.28 (d, J=17.6 Hz, 1H), 5.25 (d, J=10.6 Hz, 1H),4.83 (s, 1H), 4.41-4.37 (m, 1H), 4.02 (dd, J=16.2, 5.6 Hz 1H), 3.30 (d,J=14.9 Hz, 1H), 3.01 (d, J=14.9 Hz, 1H), 1.98 (s, 3H), 1.66 (s, 3H) ppm;¹³C-NMR (126 MHz, CDCl₃) δ 165.1 (C), 162.2 (C), 148.6 (C), 148.3 (C),131.5 (CH), 127.6 (C), 120.7 (CH), 120.4 (C), 118.4 (CH₂), 108.6 (CH),107.2 (CH), 101.6 (CH₂), 73.6 (C), 73.1 (C), 72.4 (CH), 45.2 (CH₂), 44.5(C), 42.9 (CH₂), 24.8 (CH₃), 17.5 (CH₃) ppm; IR (film) ν/cm⁻¹ 1688,1491, 1446, 1359, 1249, 1191, 1103, 1038, 929 cm⁻¹; HRMS (ESI) calcd forC₂₀H₁₉N₃O₄S₂Na⁺ (M+Na) 452.0715, found 452.0719.

Rac-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2-cyclopropyl-3,7-dimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃) δ 6.87 (s, 1H), 6.84-6.81 (app. s, 2H), 5.99 (s,2H), 4.80 (s, 1H), 3.27 (d, J=14.9 Hz, 1H), 2.93 (d, J=14.9 Hz, 1H),2.57-2.53 (m, 1H), 2.12 (s, 3H), 1.66 (s, 3H), 1.29-1.24 (m, 1H),1.06-0.97 (m, 2H), 0.96-0.90 (m, 1H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ165.7 (C), 162.3 (C), 148.6 (C), 148.3 (C), 127.6 (C), 120.7 (CH), 120.4(C), 108.6 (CH), 107.2 (CH), 101.6 (CH₂), 74.4 (C), 74.1 (C), 72.4 (CH),44.5 (C), 42.9 (CH₂), 25.8 (CH), 24.8 (CH₃), 17.8 (CH₃), 8.2 (CH₂), 7.7(CH₂) ppm; IR (film) ν/cm⁻¹ 1696, 1491, 1446, 1348, 1248, 1189, 1037,930, 735 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₉N₃O₄S₂Na⁺ (M+Na) 452.0715,found 452.0702.

Rac-(3S,6S,7S,8aS)-6-(3,4-bis(allyloxy)phenyl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃) δ 6.95 (s, 1H), 6.92-6.88 (m, 2H), 6.11-6.03 (m,2H), 5.45-5.38 (m, 2H), 5.29-5.24 (m, 2H), 4.87 (s, 1H), 4.63-4.60 (m,4H), 3.31 (d, J=14.8 Hz, 1H), 3.08 (s, 3H), 2.98 (d, J=14.8 Hz, 1H),1.95 (s, 3H), 1.66 (s, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ 165.6 (C),162.2 (C), 149.3 (C), 148.8 (C), 133.4 (CH), 133.3 (CH), 126.5 (C),120.3 (CH), 119.8, 117.9 (CH₂), 117.8 (CH₂), 113.7 (CH), 112.2 (CH),73.8 (C), 73.6 (C), 72.4 (C), 70.0 (CH₂), 69.9 (CH₂), 44.5 (C), 42.8(CH₂), 27.9 (CH₃), 25.1 (CH₃), 18.3 (CH₃) ppm; IR (film) ν/cm⁻¹ 1695,1607, 1593, 1516, 1424, 1380, 1360, 1262, 1218, 1141, 996, 919, 731cm⁻¹; HRMS (ESI) calcd for C₂₃H₂₅N₃O₄S₂Na⁺ (M+Na) 494.1184, found494.1188.

Rac-(3S,6S,7S,8aS)-6-(7-methoxybenzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexa-hydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃) δ 6.60 (s, 1H), 6.58 (s, 1H), 6.00 (m, 2H), 4.84(s, 1H), 3.89 (s, 3H), 3.31 (d, J=14.8 Hz, 1H), 3.08 (s, 3H), 2.99 (d,J=14.8 Hz, 1H), 1.95 (s, 3H), 1.67 (s, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃)δ 165.5 (C), 162.1 (C), 149.3 (C), 143.9 (C), 136.1 (C), 128.2 (C),120.2 (C), 106.5 (CH), 102.0 (CH₂), 101.3 (CH), 73.7 (C), 73.6 (C), 72.5(CH₂), 56.7 (CH₃), 44.5 (C), 42.8 (CH₂), 27.9 (CH₃), 25.2 (CH₃), 18.2(CH₃) ppm; IR (film) ν/cm⁻¹ 2984, 2250, 1696, 1637, 1512, 1453, 1358,1246, 1201, 1129, 1093, 1044, 913, 731 cm⁻¹; HRMS (ESI) calcd forC₁₉H₁₉N₃O₅S₂Na⁺ (M+Na) 456.0664, found 456.0648.

Rac-(3S,6S,7S,8aS)-6-(2,3-dihydro-1H-inden-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃) δ 7.26 (d, J=7.2 Hz, 1H), 7.20 (s, 1H), 7.15 (d,J=7.2 Hz, 1H), 4.87 (s, 1H), 3.30 (d, J=14.9 Hz, 1H), 3.07 (s, 3H), 3.00(d, J=14.9 Hz, 1H), 2.94-2.89 (m, 4H), 2.08 (app. quintet, J=7.5 Hz,2H), 1.93 (s, 3H), 1.67 (s, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ 165.8(C), 162.2 (C), 145.8 (C), 145.0 (C), 131.5 (C), 124.9 (CH), 124.8 (CH),122.9 (CH), 120.5 (C), 73.6 (C), 73.4 (C), 72.8 (CH), 44.6 (C), 43.0(CH₂), 33.0 (CH₂), 32.8 (CH₂), 27.9 (CH₃), 25.4 (CH₂), 24.8 (CH₃), 18.2(CH₃) ppm; IR (film) ν/cm⁻¹ 2941, 2251, 1696, 1440, 1359, 1254, 1202,1145, 1112, 1067, 1030, 911, 731 cm⁻¹; HRMS (ESI) calcd forC₂₀H₂₁N₃O₂S₂Na⁺ (M+Na) 422.0973, found 422.0965.

Rac-(3S,6S,7S,8aS)-2,3,7-trimethyl-1,4-dioxo-6-(1-(phenylsulfonyl)-1H-indol-3-yl)hexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile

¹H-NMR (500 MHz, CDCl₃) δ 7.96 (d, J=8.4 Hz, 1H), 7.86-7.84 (m, 3H),7.55 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.42 (t, J=7.8 Hz, 2H),7.34 (t, J=7.7 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 5.29 (s, 1H), 3.43 (d,J=14.7 Hz, 1H), 3.10 (s, 3H), 3.05 (d, J=14.7 Hz, 1H), 1.96 (s, 3H),1.70 (s, 3H) ppm; ¹³C-NMR (126 MHz, CDCl₃) δ 165.5 (C), 162.0 (C), 137.8(C), 135.3 (C), 134.2 (CH), 129.4 (CH), 128.9 (C), 127.1 (CH), 125.8(CH), 125.5 (CH), 123.8 (CH), 120.1 (C), 119.5 (CH), 116.6 (C), 114.1(CH), 73.6 (C), 73.3 (C), 64.2 (CH), 43.8 (C), 42.8 (CH₂), 28.0 (CH₃),25.2 (CH₃), 18.3 (CH₃) ppm; IR (film) ν/cm⁻¹ 2360, 1696, 1447, 1361,1214, 1176, 1120, 1095, 974, 747, 725, 684 cm⁻¹; HRMS (ESI) calcd forC₂₅H₂₂N₄O₄S₃Na⁺ (M+Na) 561.0701, found 561.0703.

Example 6 Separation of Enantiomers of ETP Products Isolation of(3S,6S,7S,8aS)- and(3R,6R,7R,8aR)-6-(benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitriles

The two enantiomers were separated by preparative chiral HPLC(stationary phase: CHIRALPAK IA (250×50 mm i.d., 5 micron), mobilephase: reagent alcohol 100%), flow rate 2.5 mL/min). The enantiomericexcess was determined by means of analytical chiral HPLC (stationaryphase CHIRALPAK IA-3 (50×4.6 mm i.d., 3 micron), mobile phase: reagentalcohol 100%, flow rate 1 mL/min, 254 nm): (3S,6S,7S,8aS)-enantiomer:t_(ret)=1.40 min; (3R,6R,7R,8aR)-enantiomer: t_(ret)=2.11 min.

Absolute configuration was assigned on the basis of CD data (FIG. 36)and existing precedent [Carmack, M.; Neubert, L. A. J. Am. Chem. Soc.1967, 89, 7134-7136. Hauser, D.; Weber, H. P.; Sigg, H. P. Helv. Chim.Acta 1970, 53, 1061-1073. Minato, H.; Matsumoto, M.; Katayama, T. J.Chem. Soc. D. 1971, 44-45. Nagarajan, R.; Woody, R. W. J. Am. Chem. Soc.1973, 95, 7212-7222. Woody, R. W. Tetrahedron 1973, 29, 1273-1283].

Example 7 Cell Culture

HT1080, 293T cells and the pancreatic cancer cell lines Panc1, BxPC3,SU.86.86 were obtained from ATCC (Manassas, Va.). Panc1, HT1080 and 293Tcells were maintained in DMEM medium (Mediatech, Manassas, Va.)supplemented with 10% heat inactivated FBS (Gemini Bio-products, WestSacramento, Calif.). BxPC3 and SU.86.86 cells were maintained inRPMI-1640 medium (Mediatech) supplemented with 10% heat inactivated FBS.

MTS Assay:

Panc1, BxPC3, or SU.86.86 cells were seeded in a 96-well plate at adensity of 7500 cells/well prior to treatment with increasing amounts ofETP69 or DMSO vehicle control. Forty-eight hours post treatment cellswere incubated with the MTS substrate (CellTiter 96 AQueous One SolutionCell Proliferation Assay, Promega, Madison, Wis.) according to themanufacturer's instructions. The absorbance was measured at 490 nm usinga 96-well plate reader (Synergy 4, Biotek), and the data were normalizedto the absorbance of DMSO-treated cells. IC₅₀ values were determinedusing GraphPad Prism's non-linear regression function. See FIGS. 11, 21,22A, 22B, 23, 24A, 24B, 24C, 25A and 25B.

Lentiviral Vector Production:

293T cells were plated at a density of 4×10⁶ cells per 10-cm culturedish. Cells were co-transfected by calcium phosphate co-precipitationwith either 20 μl of pPACK packaging plasmid mix (SBI, Mountain View,Calif.) and 15 μg of pLKO.1-SUV39H1 shRNA (TRCN0000275322, Sigma St.Louis, Mo.) or pLKO.1-non-silencing shRNA (Sigma). The culture mediumwas replaced with fresh medium after 6 h. Supernatant was collected 24 hand 48 h after transfection. To determine the viral titers, 10⁵ HT1080cells were seeded in a six-well plate and transduced with variousdilutions of the vector in the presence of 4 μg of Polybrene/ml (Sigma,St. Louis, Mo.). The culture medium was replaced 48 h later with freshmedium containing puromycin (Sigma) at a concentration of 1.5 μg/ml.Puromycin-resistant colonies were counted 10 days after transduction.The pancreatic cancer cells (Panc1, BxPC3 and SU.86.86) were transducedwith the viral vectors at a MOI of 0.5. Transduced cells were selectedwith puromycin (1.5 μg/ml for BxPC3 and SU.86.86; 2 g/ml for Panc1). SeeFIGS. 24-26.

QPCR:

Total RNA was isolated from cells using the RNeasy kit (Qiagen). TheTetro cDNA kit (Bioline) and SensiFast Probe kit (Bioline) were used toreverse-transcribe and amplify total RNA according to the manufacturer'sprotocol. The ProbeFinder software (Roche Applied Science) was used todesign the primer sets for SUV39H1, p53 and GAPDH and to select therespective probes from the Universal ProbeLibrary (Roche AppliedScience). Probe #13 and the following primers were used for the SUV39H1assay: 5′ gtcatggagtacgtgggagag (SEQ ID NO: 1) and 5′cctgacggtcgtagatctgg (SEQ ID NO:2). Probe #21 and the following primerswere used for the p53 assay: 5′ tagtgtggtggtgccctatg (SEQ ID NO:3) and5′ cacatgtagttgtagtggatggtg (SEQ ID NO:4). Probe #60 and the followingprimers were used for the GAPDH assay: 5′ agccacatcgctcagacac (SEQ IDNO:5) and 5′ gcccaatacgaccaaatcc (SEQ ID NO:6). All samples were run intriplicates. Amplifications were performed on a Bio-Rad CFX96 TouchMultiple-Color Real-time PCR Detection System. The data were normalizedto the GAPDH expression and the relative expression levels werecalculated using the 2^(−ΔΔCt) method.

Senescence Assay:

Panc1 cells were seeded at a density of 3×10⁴ cells per well in a24-well plate. The cells were then treated with 100 nM ETP69 or 0.3%DMSO (vehicle control). Panc-1 and SU.86.86 cells expressing SUV39H1shRNA or a non-targeting (NT) control shRNA were also seeded in 24-wellplates at a density of 3×10⁴ cells/well and 5×10⁴ cells/well,respectively. After 5 days, cells were washed with PBS, fixed with 3%formaldehyde/PBS, and stained over night at 37° C. with a freshlyprepared staining solution (1 mg/ml 5-bromo-4-chloro-3-indolylb-D-galactoside in 40 mM citric acid/sodium phosphate, pH 6.0, 5 mMpotassium ferrocyanide, 5 mM potassium ferricyanide, 150 mM NaCl, 2 mMMgCl₂). The blue stain indicates senescence-associated β-galactosidaseactivity. Photographs were taken with a 100× or a 20× objective underbrightfield illumination using an INFINITY2 digital CCD camera(Lumenera, Canada) mounted on a Nikon Eclipse TS100 inverted microscope.See FIGS. 29-31.

Migration (“Wound Healing”) Assay:

Panc1, BxPC3 and SU.86.86 pancreatic cancer cells expressing SUV39H1shRNA or a non-targeting (NT) control shRNA were grown in 6-well plates.Upon reaching confluence the cell monolayers were scratched with apipette tip to create uniform “wounds”. Cells were then allowed tomigrate into the denuded area. Photographs were taken with a 10×objective under brightfield illumination at 0 h and 24 h using anINFINITY2 digital CCD camera (Lumenera, Canada) mounted on a NikonEclipse TS100 inverted microscope. See FIG. 32.

Example 8 FLT3 Inhibition Studies

The kinase assays in vitro were performed with recombinant FLT3 proteinusing the HotSpot protocol (Reaction Biology Corp, Malvern, Pa.).Briefly, proteins, freshly prepared substrates and ³³P-ATP (specificactivity 0.01 μCi/μl final) were mixed in reaction buffer (20 mM HEPESpH 7.5, 10 mM MgCl₂, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mMNa₃VO₄, 2 mM DTT) in the presence of DMSO as control or S enantiomer ofETP69. The mixtures were reacted for 120 min at room temperature.Samples were transferred onto P81 ion exchange paper and filters wereextensively washed with 0.75% phosphoric acid. The radioactivities weremonitored.

Western blot analyses were performed with specific antibodies. Briefly,human A2058 melanoma, DU145 prostate, A549 non-small lung and SKOV3ovarian cancer cells were treated with ETP69. Whole-cell lysates (40 □g)or histone extracts (10 □g) were resolved by SDS-PAGE. Primary specificantibodies to histone H3 and histone H3 (trimethyl K9) were incubated inPBS (pH 7.5) with 0.1% (v/v) Tween-20 and 5% (w/v) BSA with gentleagitation overnight at 4° C. Other specific antibodies were diluted inPBS (pH 7.5) with 5% (w/v) nonfat milk and 0.1% (v/v) Tween-20 overnight at 4° C. Horseradish peroxidase-conjugated secondary antibodieswere incubated in PBS (pH 7.5) with 5% (w/v) nonfat milk and 0.1% (v/v)Tween-20 for 1 h at room temperature. Positive immuno-reactive proteinswere detected using the ECL system (Pierce, Rockford, Ill.).

For histone methyltranferase (HMT), DNA methyltransferase (DNMT) andHistone acetyltransferase (HAT) assays in vitro, human recombinant HMT,DNMT and HAT proteins were mixed with substrates in the reaction buffer(50 mM Tris-HCl (pH 8.5), 5 mM MgCl2, 50 mM NaCl, 1 mM DTT, 1 mM PMSF,1% DMSO), including histone H3, histone H4, nucleosomes, or corehistone. Racemic ETP69, S enantiomer or DMSO as a vehicle control waspreincubated in the mixture. Next, for HMTs and DNMT assays, 1 mM of³H-SAM was added to the mixture for the reaction initiation andconversion of ³H-SAM+histone L-lysine to SAH+histoneN⁶-[methyl-³H]-L-lysine was monitored with miniatured radioligand-filterbinding platform. For p300 HAT assays, the conversion ofacetyl-³H-acetyl coenzyme A to coenzyme A was monitored. The reactionswere carried out at 30° C. IC₅₀ values were determined using Excel andGraphPad Prism software.

In Vivo Xenograft Procedures for Lung Cancer, Melanoma, and OvarianCancer (See FIGS. 15A, 15B, 16A, 16B, 17A, 17B, 18A and 18B):

Human A2058 melanoma cells (3×10⁶) were resuspended in serum-freeRPMI1640 medium and subcutaneously injected into the flank of 5-6 weeksold Athymic female nude mouse (NCI). When palpable tumor sizes reachedat approximately 100 mm³, mice were divided into two groups (vehicle=5,treatment=5). Then, ETP69 was administered with intraperitoneal (IP)injection at 20 mg/kg with vehicle (10% DMSO+0.5% Teen 20+89.5% saline),once daily for 13 days. Tumor volumes were calculated by the formula1/2a×b², where a is the long diameter, and b is the short diameter.Tumor volumes correlate with tumor weights. The statistical significanceof group differences was analyzed using a Student's t-test with thetwo-tailed distribution. P values less than 0.05 were consideredstatistically significant.

Human A549 non-small lung cancer cells (5×10⁶) were resuspended inserum-free DMEM medium and Matrigel (ration of 1:1) and subcutaneouslyinjected into the flank of 5-6 weeks old femaleNOD/SCID/IL-2rg(ko)(NSG). When palpable tumor sizes reached atapproximately 50 mm³, mice were divided into two groups (vehicle=10,treatment=10). Then, ETP69 was orally administered at 10 mg/kg withvehicle (10% DMSO+30% Solutol+60% saline), once daily for 31 days. Tumorvolumes were calculated by the formula 1/2a×b², where a is the longdiameter, and b is the short diameter. Tumor volumes correlate withtumor weights. The statistical significance of group differences wasanalyzed using a Student's t-test with the two-tailed distribution. Pvalues less than 0.05 were considered statistically significant.

Human MV4-11 acute myeloid leukemia (AML) cancer cells (5×10⁶) that haveFLT-ITD mutations were resuspended in serum-free RPMI1640 medium andMatrigel (ration of 1:1) and subcutaneously injected into the flank of5-6 weeks old female NOD/SCID/IL-2rg(ko)(NSG). When palpable tumor sizesreached at approximately 50 mm³, mice were divided into three groups(vehicle=9, 5 mg/kg dose group=8, 10 dose mg/kg group=8). Then, Senantiomer was orally administered at 5 mg/kg or 10 mg/kg with vehicle(10% DMSO+30% Solutol+60% saline), once daily for 20 days. Tumor volumeswere calculated by the formula 1/2a×b², where a is the long diameter,and b is the short diameter. Tumor volumes correlate with tumor weights.The statistical significance of group differences was analyzed using aStudent's t-test with the two-tailed distribution. P values less than0.05 were considered statistically significant.

Human SKOV3 cancer cells (4×10⁶) were resuspended in serum-free McCoy'smedium and Matrigel (ration of 1:1) and subcutaneously injected into theflank of 5-6 weeks old female NOD/SCID/IL-2rg(ko)(NSG). When palpabletumor sizes reached at approximately 50 mm³, mice were divided into twogroups (vehicle=9, treatment=9). Then, ETP69 was administered with IPinjection at 2.5 mg/kg with vehicle (5% DMSO+15% Solutol+80% H₂O), oncedaily for 18 days. Tumor volumes were calculated by the formula 1/2a×b²,where a is the long diameter, and b is the short diameter. Tumor volumescorrelate with tumor weights. The statistical significance of groupdifferences was analyzed using a Student's t-test with the two-taileddistribution. P values less than 0.05 were considered statisticallysignificant.

Cell Testing Assays with ETP Derivatives in Combination with DNMTInhibitors and Multi-Kinase Inhibitors (See FIGS. 12A-12D, 13A-13C and14A-14C):

MTS assays were performed for cell viability for combination study withETP69 plus DNMT inhibitors or mutikinase inhibitor. Human SKOV3 ovarianand A549 non-small cancer cells were seeded in 96-well plates(5000/well), incubated overnight at 37° C. in 5% CO₂, and exposed toETP69 plus azacitidine, decitabine or sorafenib for 48. Dimethylsulfoxide (DMSO) was used as the vehicle control. Viable cell numberswere determined by tetrazolium conversion to its formazan dye andabsorbance was measured at 490 nm using an automated ELISA plate reader.Each experiment was performed in quadruplicate.

Induction of p16, p53, p21waf1 and p27 (FIGS. 8 and 9):

Western blot analyses were performed with specific antibodies. Briefly,human A2058 melanoma, DU145 prostate, A549 non-small lung and SKOV3ovarian cancer cells were treated with ETP69. Whole-cell lysates (40 □g)were resolved by SDS-PAGE. Primary specific antibodies to p53,p21^(WAF1), p27(Kip1), p16 and Actin were diluted in PBS (pH 7.5) with5% (w/v) nonfat milk and 0.1% (v/v) Tween-20 over night at 4° C.Horseradish peroxidase-conjugated secondary antibodies were incubated inPBS (pH 7.5) with 5% (w/v) nonfat milk and 0.1% (v/v) Tween-20 for 1 hat room temperature. Positive immuno-reactive proteins were detectedusing the ECL system (Pierce, Rockford, Ill.).

Apoptosis Determinations (FIG. 11):

Apoptosis assays of human SKOV3 ovarian cancer cells based on loss ofmembrane integrity were carried out using Annexin V-FITC. Briefly, cellswere seeded in 6-well plates, incubated overnight at 37° C. in 5% (v/v)CO₂ and exposed to ETP69 in a dose-dependent manner for 48 h. DMSO wasused as the vehicle control. Cells were analyzed using a FACScan flowcytometer to quantify fluorescence. Apoptotic cells were defined asAnnexin V-FITC positive. Each experiment was performed in quadruplicate.

IC50 Determinations for Ovarian, Liver, Pancreatic, CML, AML Cancer CellLines (See e.g. FIGS. 4, 6A-6C, 21, 22A, 22B, 23, 24A-24C, 25A, 25B and34):

MTS assays were performed for cell viability. SKOV3 ovarian cancer,Huh-7 hepatocellular carcinoma, MIA-PaCa2 pancreatic cancer, KCL-22 CML,T315I mutant KCL-22 CML, MOLM-13 AML and MV4-11 AML cells were seeded in96-well plates (5000 cells/well for solid tumors, 10000 cells/well forblood tumors), incubated overnight at 37° C. in 5% CO₂, and exposed toracemic ETP69 or S enantiomer in a dose-dependent manner for 48 h.Dimethyl sulfoxide (DMSO) was used as the vehicle control. Viable cellnumbers were determined by tetrazolium conversion to its formazan dyeand absorbance was measured at 490 nm using an automated ELISA platereader. Each experiment was performed in quadruplicate.

Example 9

ETP Analogue Activity

It was found that the prepared ETPs show different IC₅₀ values rangingfrom 0.1 to >5 μM. In general, the aromatic rings incorporated at anearly stage seem to have little effect on the observed activities;however, the presence of a nitrile group rather than different estersenhances the potency of such compounds significantly. As such ETP69 wasidentified as a promising lead structure with an IC₅₀ falling in betweenthe monomeric and dimeric ETP natural products (−0.6 and 0.07 μM).

ETP69 was screened against a number of transferases and demonstrateabout ten times more potency against several transferases than chaetocinitself. In addition, the data obtained suggests that ETP69 is selectiveagainst histone methyltransferases (SUV39H1; G9a) over histoneacetylases (p300) and DNA methyl transferases (DNMT1).

ETP69 shows no significant toxicity up to concentrations of 20 mg/kgwith intraperitoneal injection (IP) or oral administration.

VI. References

-   Iwasa, E.; Hamashima, Y.; Sodeoka, M. J. Isr. Chem. 2011, 51,    420-433.-   Isham, C. R.; Tibodeau, J. D.; Jin, W.; Xu, R.; Timm, M. M.;    Bible, K. C. Blood 2007, 109, 2579-2588.-   Scharf, D. H.; Remme, N.; Heinekamp, T.; Hortschansky, P.;    Brakhage, A. A.; Hertweck, C. J. Am. Chem. Soc. 2010, 132,    10136-10141.-   Cook, K. M.; Hilton, S. T.; Mecinovic, J.; Motherwell, W. B.;    Figg, W. D.; Schofield, C. J. J. Biomol. Chem. 2008, 284,    26831-26838.-   Kishi, Y.; Nakatsuka, S.; Fukuyama, T.; Havel, M. J. Am. Chem. Soc.    1973, 95, 6493-6495.-   Kishi, Y.; Nakatsuka, S.; Fukuyama, T. J. Am. Chem. Soc. 1973, 95,    6492-6493.-   Kim, J.; Ashenhurst, J. A.; Movassaghi, M. Science 2009, 10,    238-241.-   Iwasa, E.; Hamashima, Y.; Fujishiro, S.; Higuchi, E.; Ito, A.;    Yoshida, M.; Sodeoka, M. J. Am. Chem. Soc. 2010, 132, 4078-4079.-   Kim, J.; Movassaghi, M. J. Am. Chem. Soc. 2010, 132, 14376-14378.-   DeLorbe, J. E.; Jabri, S. Y.; Mennen, S. M.; Overman, L. E.; Zhang,    F.-L. J. Am. Chem. Soc. 2011, 133, 6549-6552.-   Block, K. M.; Wang, H.; Szabo, L. Z.; Polaske, N. W.; Henchey, L.    K.; Dubey, R.; Kushal, S.; Laszlo, C. F.; Makhoul, J.; Song, Z.;    Meuillet, E. J.; Olenyuk, B. Z. J Am. Chem. Soc. 2009, 131,    18078-18088.-   Tsuge, O.; Kanemasa, S.; Yoshioka, M. J. Org. Chem. 1988, 53,    1384-1391.-   Adrio, J.; Carretero, J. C. Chem. Commun. 2011, 47, 6784-6794.-   Nobuyuki, K.; Ryuzou, A.; Junichi, U. Tetrahedron Lett. 2009, 50,    6580-6583.-   Firouzabadi, H.; Vessal, B, Naderi, M. Tetrahedron Lett. 1982, 23,    1847-1850.-   Friedrich, A.; Jainta, M.; Nieger, M.; Braese, S. Synlett 2007, 13,    2127-2729.-   Nicolaou, K. C.; Totokotsopoulos, S.; Giguerre, D.; Sun, Y.-P.;    Sarlah, D. J. Am. Chem. Soc. 2011, 133, 8150-8153.-   Nicolaou, K. C.; Totokotsopoulos, S.; Giguerre, D.; Sun, Y.-P.    Angew. Chem. Int. Ed. 2012, 124, 752-756.-   Seephonkai, P.; Kongsaeree, P.; Prabpai, S.; Isaka, M.;    Thebtaranonth, Y. Org. Lett. 2006, 14, 3073-3075.-   Codelli, J. A.; Puchlopek, A. L. A.; Reisman, S. E. J. Am. Chem.    Soc. 2012, 134, 1930-1933.-   Öhler, E.; Tataruch, F.; Schmidt, U. Chem. Ber. 1973, 106, 396-398.

VII. Embodiments Embodiment 1

A compound having the formula:

-   -   wherein, p is 2, 3 or 4; R¹ is hydrogen, halogen, —N₃, —CF₃,        —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33A), —NR^(34A)R^(35A),        —COOR^(33A), —CONR^(34A)R^(35A), —NO₂, —SR^(36A),        —SO_(n1)R^(34A), —SO_(n1)OR^(34A), —SO_(n1)NR^(34A)R^(35A),        —NHNR^(34A)R^(35A), —ONR^(34A)R^(35A), —NHC(O)NHNR^(34A)R^(35A),        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;        R² is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(33B), —NR^(34B)R^(35B), —COOR^(33B),        —CONR^(34B)R^(35B), —NO₂, —SR^(36B), —SO_(n2)R^(34b),        —SO_(n2)OR^(34B), —SO_(n2)NR^(34B)R^(35B), —NHNR^(34B)R^(35B),        —ONR^(34B)R^(35B), —NHC(O)NHNR^(34B)R^(35B), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl; R³ is        hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,        —OR³³C, —NR^(34C)R^(35C), —COOR^(33C), —CONR^(34C)R³⁵, —NO₂,        —SR^(36C), —SO_(n3)R³⁴, —SO_(n3)OR³⁴, —SO_(n3)NR^(34C)R³⁵,        —NHNR^(34C)R³⁵, —ONR^(34C)R^(35C), —NHC(O)NHNR^(34C)R^(35C),        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;        R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,        —CHO, —OR^(33D), —NR^(34D)R^(35D), —COOR^(33D),        —CONR^(34D)R^(35D), —NO₂, —SR^(36D), —SO_(n4)R^(34D),        —SO_(n4)OR^(34D), —SO_(n4)NR^(34D)R^(35D), —NHNR^(34D)R^(35D),        —ONR^(34D)R^(35D), —NHC(O)NHNR^(34D)R^(35D), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl; R⁵ is        hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,        —OR^(33E), —NR^(34E)R^(35E), —COOR^(33E), —CONR^(34E)R^(35E),        —NO₂, —SR^(36E), —SO_(n5)R^(34E), —SO_(n5)OR^(34E)R^(35E),        —SO_(n5)NR^(34E)R^(35E), —NHNR^(35E)R^(35E), —ONR^(34E)R^(35E),        —NHC(O)NHNR^(34E)R^(35E), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl; R⁶ is hydrogen,        halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33F),        —NR^(34F)R^(35F), —COOR^(33F), —CONR^(34F)R^(35F), —NO₂,        —SR^(36F), —SO_(n6)R^(34F), —SO_(n6)OR^(34F),        —SO_(n6)NR^(34F)R^(35F), —NHNR^(34F)R^(35F), —ONR^(34F)R^(35F),        —NHC(O)NHNR^(34F)R^(35F), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl; R¹⁶ is hydrogen,        halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33G),        —NR^(34G)R^(35G), —COOR^(33G), —CONR^(34G)R^(35G), —NO₂,        —SR^(36G), —SO_(n7)R^(34G), —SO_(n7)OR^(34G),        —SO_(n7)NR^(34G)R^(35G), —NHNR^(34G)R^(35G), —ONR^(34G)R^(35G),        —NHC(O)NHNR^(34G)R^(35G), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl; R¹⁸ is hydrogen,        halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33H),        —NR^(34H)R^(35H), —COOR^(33H), —CONR^(34H)R^(35H), —NO₂,        —SR^(36H), —SO_(n8)R^(34H), —SO_(n8)OR^(34H),        —SO_(n8)NR^(34H)R^(35H), —NHNR^(35H), —ONR^(34H)R^(35H),        —ONR^(34H)R^(35H), —NHC(O)NHNR^(34H)R^(35H), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl; R^(33A),        R^(34A), R^(35A), R^(36A), R^(33B), R^(34B), R^(35B), R^(36B),        R^(33C), R^(34C), R^(35C), R^(36C), R^(33D), R^(34D), R^(35D),        R^(36D), R^(33E), R^(34E), R^(35E), R^(36E), R^(33F), R^(34F),        R^(35F), R^(36F), R^(33G), R^(34G), R^(35G), R^(36G), R^(33H),        R^(34H), R^(35H), and R^(36H) are independently hydrogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;        and n1, n2, n3, n4, n5, n6, n7, and n8 are independently 1 or 2.

Embodiment 2

The compound of embodiment 1, wherein R¹⁸ is substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

Embodiment 3

The compound of embodiments 1 or 2, wherein R¹⁸ is R^(18a)-substitutedor unsubstituted 5 membered heterocycloalkyl, R^(18a)-substituted orunsubstituted 6 membered aryl, R^(18a)-substituted or unsubstituted 6membered heteroaryl, R^(18a)-substituted or unsubstituted 6,6 fused ringaryl-heterocycloalkyl, R^(18a)-substituted or unsubstituted 6,5 fusedring aryl-heterocycloalkyl, R^(18a)-substituted or unsubstituted 5,6fused ring aryl-heterocycloalkyl; R^(18a) is halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl,—SO₃H, —SO₄H, —SO₂Ph, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,R^(18b)-substituted or unsubstituted C₁-C₈ alkyl, R^(18b)-substituted orunsubstituted 2 to 8 membered heteroalkyl, R^(18b)-substituted orunsubstituted 3 to 8 membered cycloalkyl, R^(18b)-substituted orunsubstituted 3 to 6 membered heterocycloalkyl, R^(18b)-substituted orunsubstituted 5 to 6 membered aryl, or R^(18b)-substituted orunsubstituted 5 to 6 membered heteroaryl; and R^(18b) is halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,unsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 membered heteroalkyl,unsubstituted 3 to 8 membered cycloalkyl, unsubstituted 3 to 6 memberedheterocycloalkyl, unsubstituted 5 to 6 membered aryl, or unsubstituted 5to 6 membered heteroaryl.

Embodiment 4

The compound of embodiments 1-3, wherein R^(18a) is halogen, —SO₂Ph,R^(18b)-substituted or unsubstituted C₁-C₅ alkyl, or R^(18b)-substitutedor unsubstituted 2 to 5 membered heteroalkyl, unsubstituted 5 to 6membered heterocycloalkyl, or unsubstituted phenyl; and R^(18b) ishalogen, unsubstituted C₁-C₈ alkyl, or unsubstituted 2 to 8 memberedheteroalkyl.

Embodiment 5

The compound of embodiments 1-4, wherein said R^(18a)-substituted 5membered heterocycloalkyl is an R^(18a)-substituted thiophenyl,R^(18a)-substituted thiazolyl, R^(18a)-substituted oxazolyl, orR^(18a)-substituted imidazolyl; and R^(18a) is halogen, unsubstitutedC₁-C₅ alkyl, or unsubstituted 2 to 5 membered heteroalkyl.

Embodiment 6

The compound of embodiment 1-3, wherein R¹⁸ is unsubstitutedheterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

Embodiment 7

The compound of any one of embodiments 1 to 6, wherein R¹⁶ is hydrogen.

Embodiment 8

The compound of any one of embodiments 1 to 6, wherein R³ and R⁴ arehydrogen.

Embodiment 9

The compound of any one of embodiments 1 to 6, wherein R¹ is —CN orunsubstituted 2 to 5 membered heteroalkyl.

Embodiment 10

The compound of embodiments 1-9, wherein R¹ is —CN.

Embodiment 11

The compound of embodiments 1-9, wherein R¹ is —COOR^(33A), whereinR^(33A) is C₁-C₃ unsubstituted alkyl.

Embodiment 12

The compound of any one of embodiments 1 to 6 or 10-11, wherein R² is—N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂Ph, —SO₂NH₂, —NHNH₂, —ONH₂,R^(2a)-substituted or unsubstituted C₁-C₃ alkyl, or 2 to 3 memberedR^(2a)-substituted or unsubstituted heteroalkyl; R^(2a) is —N₃, —CF₃,—CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂Ph, —SO₂NH₂, —NHNH₂, —ONH₂, R^(2b)-substitutedor unsubstituted C₁-C₅ alkyl, R^(2b)-substituted or unsubstituted 2 to 5membered heteroalkyl, R^(2b)-substituted or unsubstituted 3 to 6membered heterocycloalkyl, R^(2b)-substituted or unsubstituted 5 or 6membered aryl, or R^(2b)-substituted or unsubstituted 5 or 6 memberedheteroaryl; and R^(2b) is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, unsubstituted C₁-C₈ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted 3 to 8 memberedcycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl,unsubstituted 5 to 6 membered aryl, or unsubstituted 5 to 6 memberedheteroaryl.

Embodiment 13

The compound of any one of embodiments 1 to 6 or 10-11, wherein R² ismethyl or methoxy.

Embodiment 14

The compound of any one of embodiments 1 to 6 or 10-11, wherein R² isR^(2a)-substituted or unsubstituted C₁-C₅ alkyl, or R^(2a)-substitutedor unsubstituted 2 to 5 membered heteroalkyl, and R^(2a) isunsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted 5 or 6membered aryl, or unsubstituted 5 or 6 membered heteroaryl.

Embodiment 15

The compound of any one of embodiments 1 to 6 or 10-11, wherein R^(2a)is unsubstituted pyridinyl.

Embodiment 16

The compound of any one of embodiments 1 to 6 or 10 to 11, wherein R² isC₁-C₅ substituted or unsubstituted heteroalkyl.

Embodiment 17

The compound of any one of embodiments 1 to 6 or 10-11, wherein R² is apolar substituent.

Embodiment 18

The compound of embodiments 1-17, wherein R⁵ and R⁶ are independentlyhydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,unsubstituted alkyl, or unsubstituted cycloalkyl.

Embodiment 19

The compound of embodiments 1-18, wherein R⁵ and R⁶ are independentlyhydrogen, unsubstituted C₁-C₃ alkyl or membered 3 to 5 cycloalkyl.

Embodiment 20

The compound of embodiments 1-18, wherein R⁵ and R⁶ are independentlyhydrogen, methyl, ethyl, allyl, or cyclopropyl.

Embodiment 21

The compound of any one of embodiments 1 to 6, 10 to 11, or 18, whereinp is 2.

Embodiment 22

The compound of embodiments 1-21 having the formula

wherein, X³ is N or CR⁷; X⁴ is N or CR⁸; X⁵ is N or CR⁹; R⁷ is hydrogen,halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33I),—NR^(34I)R^(35I), —COOR^(33I), —CONR^(34I)R^(35I), —NO₂, —SR^(36I),—SO_(n9)R^(34I), —SO_(n9)OR^(34I), —SO_(n9)NR^(34I)R^(35I),—NHNR^(34I)R^(35I), —ONR^(34I)R^(35I), —NHC(O)NHNR^(34I)R^(35I),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁸ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR³³, —NR^(34J)R^(35J),—COOR^(33J), —CONR^(34J)R^(35J), —NO₂, —SR^(36J), —SO_(n10)R^(34J),—SO_(n10)OR^(34J), —SO₁₀NR^(34J)R^(35J), —NHNR^(34J)R^(35J),—ONR^(34J)R^(35J), —NHC(O)NHNR^(34J)R^(35J), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33K), —NR^(34K)R^(35K), —COOR^(33K),—CONR^(34K)R^(35K), —NO₂, —SR^(36K), —SO_(n11)R^(34K),—SO_(n11)OR^(34K)K, —SO_(n11)NR^(34K)R^(35K), —NHNR^(34K)R^(35K),—ONR^(34K)R^(35K), —NHC(O)NHNR^(34K)R^(35K), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R¹⁰ and R¹¹ are independently hydrogen,halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33L),—NR^(34L)R^(35L), —COOR^(33L), —CONR^(34L)R^(35L), —NO₂, —SR^(36L),—SO_(n12)R^(34L), —SO_(n12)OR^(34L), —SO_(n12)NR^(34L)R^(35L),—NHNR^(34L)R^(35L), —ONR^(34L)R^(35L), —NHC(O)NHNR^(34L)R^(35L),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or are optionally joinedtogether to form a substituted or unsubstituted cycloalkyl, asubstituted or unsubstituted heterocycloalkyl, a substituted orunsubstituted aryl, or a substituted or unsubstituted heteroaryl;R^(33I), R^(34I), R^(35I), R^(36I), R^(33J), R^(34J), R^(35J), R^(36J),R^(33K), R^(34K), R^(35K)R^(36K), R^(33L), R^(34L), R^(35L), andR^(36L), are independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; andn9, n10, n11, and n12 are independently 1 or 2.

Embodiment 23

The compound of embodiments 1-22 having the formula:

Embodiment 24

The compound of embodiments 1-22 having the formula:

Embodiment 25

The compound of embodiments 1-22, wherein R¹ is —CN or unsubstituted 2to 5 membered heteroalkyl.

Embodiment 26

The compound of any one of embodiments 1-25, wherein R³ and R⁴ arehydrogen.

Embodiment 27

The compound of embodiments 1-22 having formula:

wherein, R⁸ is hydrogen or —OR³³; R⁹, R¹⁰, and R¹¹ are independentlyhydrogen or halogen; and R³³ is hydrogen, or unsubstituted alkyl.

Embodiment 28

The compound of embodiments 1 or 22 having formula:

wherein, X¹ is CR²¹R^(21A), O, NR^(21A), or S; X² is CR²²R^(22A), O,NR^(22A), or S; R¹², R¹³, R¹⁴, R¹⁵, R²¹, R^(21A), R²², and R^(22A) areindependently hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OR^(33M), —NR^(34M)R^(35M), —COOR^(33M), —CONR^(34M)R^(35M),—NO₂, —SR^(36M), —SO_(n13)R^(34M), —SO_(n13)OR^(34M),—SO_(n13)NR^(34M)R^(35M), —NHNR^(34M)R^(35M), —ONR^(34M)R^(35M),—NHC(O)NHNR^(34M)R^(35M), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(33M), R^(34M), R^(35M), and R^(36M) are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and n13 is 1 or 2.

Embodiment 29

The compound of embodiment 28 having formula:

Embodiment 30

The compound of embodiments 28-29, wherein R¹ is —CN or unsubstituted 2to 5 membered heterocycloalkyl.

Embodiment 31

The compound of any one of embodiments 28-30, wherein R³ and R⁴ arehydrogen.

Embodiment 32

The compound of any one of embodiments 28-30, wherein R¹⁰ and R¹¹ arehydrogen.

Embodiment 33

The compound of any one of embodiments 28-30, wherein R¹², R¹³, R¹⁴ andR¹⁵ are hydrogen.

Embodiment 34

The compound of embodiments 28-33 having formula:

Embodiment 35

The compound of embodiment 1 having formula:

wherein, X⁶ is CR²¹ or N; X⁷ is CR²²R²³, S, O, or NR²³; R¹⁹, R²⁰, R²¹,R²² and R²³ are independently hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33M), —NR^(34M)R^(35M), —COOR^(33M),—CONR^(34M)R^(35M), —NO₂, —SR^(36M), —SO_(n13)R^(34M), —SO_(n3)OR^(34M),—SO_(n13)NR^(34M)R^(35M), —NHNR^(34M)R^(35M), —ONR^(34M)R^(35M),—NHC(O)NHNR^(34M)R^(35M), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(33M), R^(34M), R^(35M), and R^(36M) are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and n13 is 1 or 2.

Embodiment 36

The compound of any one of embodiments 1 or 35 having formula:

Embodiment 37

The compound of embodiments 35-36, wherein R¹ is —CN or unsubstituted 2to 5 membered heteroalkyl.

Embodiment 38

The compound of any one of embodiments 35 to 37, wherein R³ and R⁴ arehydrogen.

Embodiment 39

The compound of any one of embodiments 35 to 37, wherein R¹⁹ and R²⁰ arehydrogen.

Embodiment 40

The compound of embodiment 1 having formula:

wherein, X¹ is CR²¹R^(21A), O, NR^(21A), or S; X² is CR²²R^(22A), O,NR^(22A), or S; R⁷ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(33I), —NR^(34I)R^(35I), —COOR³³, —CONR^(34I)R^(35I),—NO₂, —SR^(36I), —SO_(n9)R³⁴, —SO_(n9)OR^(34I), —SO₉NR^(34I)R^(35I),—NHNR^(34I)R^(35I), —ONR^(34I)R^(35I), —NHC(O)NHNR^(34I)R^(35I),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹⁰ and R¹¹ are independentlyhydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33L),—NR^(34L)R^(35L), —COOR^(33L), —CONR^(34L)R^(35L), —NO₂, —SR^(36L),—SO_(n12)R^(34L), —SO_(n12)OR^(34L), —SO_(n12)NR^(34L)R^(35L),—NHNR^(34L)R^(35L), —ONR^(34L)R^(35L), —NHC(O)NHNR^(34L)R^(35L),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or are optionally joinedtogether to form a substituted or unsubstituted cycloalkyl, asubstituted or unsubstituted heterocycloalkyl, a substituted orunsubstituted aryl, or a substituted or unsubstituted heteroaryl; R¹²,R¹³, R²¹, R^(21A), R²² and R^(22A) are independently hydrogen, halogen,—N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33M), —NR^(34M)R^(35M),—COOR^(33M), —CONR^(34M)R^(35M), —NO₂, —SR^(36M), —SO_(n13)R^(34M),—SO_(n13)OR^(34M), —SO_(n13)NR^(34M), —NHNR^(34M)R^(35M),—ONR^(34M)R^(35M), —NHC(O)NHNR^(34M)R^(35M), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(33M), R^(34M), R^(35M), and R^(36M) areindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; and n9,n11, and n13 are independently 1 or 2.

Embodiment 41

The compound of embodiment 40 having formula:

Embodiment 42

The compound of embodiments 40-41 having formula:

Embodiment 43

The compound of embodiments 40-42 having formula:

Embodiment 44

The compound of embodiments 40-43, wherein R¹ is —CN or unsubstituted 2to 5 membered heteroalkyl.

Embodiment 45

The compound of any one of embodiments 40 to 44, wherein R³ and R⁴ arehydrogen.

Embodiment 46

The compound of any one of embodiments 40 to 45, wherein R¹² and R¹³ arehydrogen.

Embodiment 47

The compound of any one of embodiments 40 to 46, wherein R¹⁰ and R¹¹ arehydrogen.

Embodiment 48

The compound of any one of embodiments 1 or 40-47 having formula:

Embodiment 49

The compound of any one of embodiments 1 or 40-47 having formula:

wherein; R⁵ is unsubstituted 3 to 5 membered cycloalkyl, orR^(5a)-substituted or unsubstituted C₁-C₅ alkyl; R^(5a) is unsubstituted2 to 5 membered heteroalkyl or 5 to 6 membered heterocycloalkyl, and pis 2 or 3.

Embodiment 50

The compound of any one of embodiments 1 or 40-49 having formula:

Embodiment 51

The compound of embodiment 1 having formula:

wherein, X¹ is CR²¹R^(21A), O, NR^(21A), or S; X² is CR²²R^(22A), O,NR^(22A), or S; R⁷ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR³³, —NR^(34I)R^(35I), —COOR³³, —CONR^(34I)R^(35I), —NO₂,—SR^(36I), —SO_(n9)R³⁴, —SO_(n9)OR^(34I), —SO₉NR^(34I)R^(35I),—NHNR^(34I)R^(35I), —ONR^(34I)R^(35I), —NHC(O)NHNR^(34I)R^(35I),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹¹ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33L), —NR^(34L)R^(35L),—COOR^(33L), —CONR^(34L)R^(35L), —NO₂, —SR^(36L), —SO_(n2)R^(34L),—SO_(n12)OR^(34L), —SO_(n12)NR^(34L)R^(35L), —NHNR^(34L)R^(35L),—ONR^(34L)R^(35L), —NHC(O)NHNR^(34L)R^(35L), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl, or are optionally joined together to form asubstituted or unsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, or a substitutedor unsubstituted heteroaryl; R¹², R¹³, R²¹, R^(21A), R²², and R^(22A)are independently hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OR^(33M), —NR^(34M)R^(35M), —COOR^(33M), —CONR^(34M)R^(35M),—NO₂, —SR^(36M), —SO_(n13)R^(34M), —SO_(n13)OR^(34M),—SO_(n13)NR^(34M)R^(35M), —NHNR^(34M)R^(35M), —ONR^(34M)R^(35M),—NHC(O)NHNR^(34M)R^(35M), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹⁷is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(33P), —NR^(34P)R^(35P), —COOR^(33P), —CONR^(34P)R^(35P), —NO₂,—SR^(36P), —SO_(n15)R^(34P), —SO_(n15)OR^(34P),—SO_(n15)NR^(34P)R^(35P), —NHNR^(34P)R^(35P), —ONR^(34P)R^(35P),—NHC(O)NHNR^(34P)R^(35P), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl, orare optionally bonded together to form a substituted or unsubstitutedcycloalkyl, a substituted or unsubstituted heterocycloalkyl, asubstituted or unsubstituted aryl, or a substituted or unsubstitutedheteroaryl; R³³, R^(34I), R^(35I), R^(36I), R^(33L), R^(34L). R^(35L),R^(36L), R^(33M), R^(34M), R^(35M), R^(36M), R^(33P), R^(34P), R^(35P),and R^(36P) are independently hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; and n9, n12, n13 and n15 are independently 1 or 2.

Embodiment 52

The compound of embodiment 51 having formula:

Embodiment 53

The compound of embodiments 51-52, wherein R¹ is —CN or unsubstituted 2to 5 membered heteroalkyl.

Embodiment 54

The compound of any one of embodiments 51 to 53, wherein R³ and R⁴ arehydrogen.

Embodiment 55

The compound of any one of embodiments 51 to 53, wherein R¹² and R¹³ arehydrogen.

Embodiment 56

The compound of any one of embodiments 51 to 53, wherein R⁷, R¹⁰, andR¹⁷ are hydrogen.

Embodiment 57

The compound of embodiments 51-56 having formula:

Embodiment 58

The compound of any one of embodiments 1-57, wherein R² is a polarsubstituent.

Embodiment 59

The compound of any one of embodiments 1-58, wherein R² is —N₃, —CF₃,—CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂Ph, —SO₂NH₂, —NHNH₂, —ONH₂, R^(2a)-substitutedor unsubstituted C₁-C₃ alkyl, or 1 to 3 membered R^(2a)-substituted orunsubstituted heteroalkyl; R^(2a) is —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂Ph,—SO₂NH₂, —NHNH₂, —ONH₂, R^(2b)-substituted or unsubstituted C₁-C₅ alkyl,R^(2b)-substituted or unsubstituted 2 to 5 membered heteroalkyl,R^(2b)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(2b)-substituted or unsubstituted 5 or 6 membered aryl, orR^(2b)-substituted or unsubstituted 5 or 6 membered heteroaryl; R^(2b)is halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, unsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 memberedheteroalkyl, unsubstituted 3 to 8 membered cycloalkyl, unsubstituted 3to 6 membered heterocycloalkyl, unsubstituted 5 to 6 membered aryl, orunsubstituted 5 to 6 membered heteroaryl.

Embodiment 60

The compound of any one of embodiments 1-59, wherein R² isR^(2a)-substituted or unsubstituted C₁-C₃ alkyl, or 2 to 3 memberedR^(2a)-substituted or unsubstituted heteroalkyl, wherein R^(2a) isunsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted 5 or 6membered aryl, or unsubstituted 5 or 6 membered heteroaryl.

Embodiment 61

The compound of any one of embodiments 1-60, wherein R² is unsubstitutedmethyl or unsubstituted methoxy.

Embodiment 62

The compound of any one of embodiments 1-61, wherein R^(2a) isunsubstituted pyridine.

Embodiment 63

The compound of any one of embodiments 1-62, wherein R⁵ and R⁶ areindependently hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, unsubstituted alkyl, or unsubstitutedcycloalkyl.

Embodiment 64

The compound of any one of embodiments 1-63, wherein R⁵ and R⁶ areindependently hydrogen, C₁-C₃ unsubstituted alkyl or 3 to 5 memberedcycloalkyl.

Embodiment 65

The compound of any one of embodiments 1-64, wherein R⁵ and R⁶ areindependently hydrogen, unsubstituted methyl, unsubstituted ethyl,unsubstituted allyl, or unsubstituted cyclopropyl.

Embodiment 66

A compound having formula:

wherein R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OR^(33A), —NR^(34A)R^(35A), —COOR^(33A), —CONR^(34A)R^(35A),—NO₂, —SR^(36A), —SO_(n1)R^(34A), —SO_(n1)OR^(34A),—SO_(n1)NR^(34A)R^(35A), —NHNR^(34A)R^(35A), —ONR^(34A)R^(35A),—NHC(O)NHNR^(34A)R^(35A), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R² ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33B),—NR^(34B)R^(35B), —COOR^(33B), —CONR^(34B)R^(35B), —NO₂, —SR^(36B),—SO₂R^(34b), —SO_(n2)OR^(34B), —SO_(n2)NR^(34B)R^(35B),—NHNR^(34B)R^(35B), —ONR^(34B)R^(35B), —NHC(O)NHNR^(34B)R^(35B),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R³ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33C), —NR^(34C)R^(35C),—COOR^(33C), —CONR^(34C)R^(35C), —NO₂, —SR^(36C), —SO₃R^(34C),—SO_(n3)OR^(34C), —SO_(n3)NR^(34C)R^(35C), —NHNR^(34C)R^(35C).—ONR^(34C)R^(35C), —NHC(O)NHNR^(34C)R^(35C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33D), —NR^(34D)R^(35D), —COOR^(33D),—CONR^(34D)R^(35D), —NO₂, —SR^(36D), —SO_(n4)R^(34D), —SO_(n4)OR^(34D),—SO_(n4)NR^(34D)R^(35D), —NHNR^(34D)R^(35D), —ONR^(34D)R^(35D),—NHC(O)NHNR^(34D)R^(35D), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33E),—NR^(34E)R^(35E), —COOR^(33E), —CONR^(34E)R^(35E), —NO₂, —SR^(36E),—SO_(n5)R^(34E), —SO_(n5)OR^(34E), —SO_(n5)NR^(34E)R^(35E),—NHNR^(34E)R^(35E), —ONR^(34E)R^(35E), —NHC(O)NHNR^(34E)R^(35E),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁶ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33F), —NR^(34F)R^(35F),—COOR^(33F), —CONR^(34F)R^(35F), —NO₂, —SR^(36F), —SO_(n6)R^(34F),—SO_(n6)OR^(34F), —SO_(n6)NR^(34F)R^(35F), —NHNR^(34F)R^(35F),—ONR^(34F)R^(35F), —NHC(O)NHNR^(34F)R^(35F), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R¹⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33G), —NR^(34G)R^(35G), —COOR^(33G),—CONR^(34G)R^(35G), —NO₂, —SR^(36G), —SO_(n7)R^(34G), —SO_(n7)OR^(34G),—SO_(n7)NR^(34G)R^(35G), —NHNR^(34G)R^(35G), —ONR^(34G)R^(35G),—NHC(O)NHNR^(34G)R^(35G), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹⁸is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(33H), —NR^(34H)R^(35H), —COOR^(33H), —CONR^(34H)R^(35H), —NO₂,—SR^(36H), —SO_(n8)R^(34H)SO_(n8)OR^(34H), —SO_(n8)NR^(34H)R^(35H),—NHNR^(34H)R^(35H), —ONR^(34H)R^(35H), —NHC(O)NHNR^(34H)R^(35H),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(33A), R^(34A), R^(35A),R^(36A), R^(33B), R^(34B), R^(35B), R^(36B), R^(33C), R^(34C), R^(35C),R^(36C), R^(33D), R^(34D), R^(35D), R^(36D), R^(33E), R^(34E), R^(35E),R^(36E), R^(33F), R^(34F), R^(35F), R^(36F), R^(33G), R^(34G), R^(35G),R^(36G), R^(33H), R^(34H), R^(35H), and R^(36H) are independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; n1, n2,n3, n4, n5, n6, n7, and n8 are independently 1 or 2; and R²⁵ and R²⁶ areindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

Embodiment 67

The compound of embodiment 66 having the formula:

wherein, X³ is N or CR⁷; X⁴ is N or CR⁸; X⁵ is N or CR⁹; R⁷ is hydrogen,halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33I),—NR^(34I)R^(35I), —COOR^(33I), —CONR^(34I)R^(35I), —NO₂, —SR^(36I),—SO_(n9)R^(34I), —SO_(n9)OR^(34I), —SO_(n9)NR^(34I)R^(35I),—NHNR^(34I)R^(35I), —ONR^(34I)R^(35I), —NHC(O)NHNR^(34I)R^(35I),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁸ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR³³, —NR^(34J)R^(35J),—COOR^(33J), —CONR^(34J)R^(35J), —NO₂, —SR^(36J), —SO_(n10)R^(34J),—SO_(n10)OR^(34J), —SO_(n10)NR^(34J)R^(35J), —NHNR^(34J)R³⁵,—ONR^(34J)R³⁵, —NHC(O)NHNR^(34J)R^(35J), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OR^(33K), —NR^(34K)R^(35K), —COOR^(33K), —CONR^(34K)R^(35K),—NO₂, —SR^(36K), —SO_(n11)R^(34K), —SO_(n11)OR³⁴K,—SO_(n11)NR^(34K)R^(35K), —NHNR^(34K)R^(35K), —ONR^(34K)R^(35K),—NHC(O)NHNR^(34K)R^(35K), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹⁰and R¹¹ are independently hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —CHO, —OR^(33L), —NR^(34L)R^(35L), —COOR^(33L),—CONR^(34L)R^(35L), —NO₂, —SR^(36L), —SO_(n12)R^(34L),—SO_(n12)OR^(34L), —SO_(n12)NR^(34L)R^(35L), —NHNR^(34L)R^(35L),—ONR^(34L)R^(35L), —NHC(O)NHNR^(34L)R^(35L), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl, or are optionally joined together to form asubstituted or unsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, or a substitutedor unsubstituted heteroaryl; R^(33I), R^(34I), R^(35I), R^(36I),R^(33J), R^(34J), R^(35J), R^(36J), R^(33K), R^(34K), R^(35K), R^(36K),R^(33L), R^(34L), R^(35L), and R^(36L), are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and n9, n10, n11, and n12 areindependently 1 or 2.

Embodiment 68

The compound of embodiments 66 or 67 having the formula

Embodiment 69

The compound of embodiments 66-68 having the formula

X⁶ is CR²¹ or N; X⁶ is CR²¹ or N; X⁷ is CR²²R²³, S, or NR²³; R¹⁹, R²⁰,R²¹, R²² and R²³ are independently hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33M), —NR^(34M)R^(35M), —COOR^(33M),—CONR^(34M)R^(35M), —NO₂, —SR^(36M), —SO_(n13)R^(34M), —SO_(n3)OR^(34M),—SO_(n13)NR^(34M)R^(35M), —NHNR^(34M)R^(35M), —ONR^(34M)R^(35M),—NHC(O)NHNR^(34M)R^(35M), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(33M), R^(34M), R^(35M), and R^(36M) are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and n13 is 1 or 2.

Embodiment 70

The compound of embodiments 66-69 having the formula:

Embodiment 71

The compound of embodiments 66-70 having the formula:

wherein X¹ is CR²¹R^(21A), O, NR^(21A), or S; X² is CR²²R^(22A), O,NR^(22A), or S; and R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A)are independently hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OR^(33M), —NR^(34M)R^(35M), —COOR^(33M), —CONR^(34M)R^(35M),—NO₂, —SR^(36M), —SO_(n13)R^(34M), —SO_(n13)OR^(34M),—SO_(n13)NR^(34M)R^(35M), —NHNR^(34M)R^(35M), —ONR^(34M)R^(35M),—NHC(O)NHNR^(34M)R^(35M), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(33M), R^(34M), R^(35M), and R^(36M) are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and n13 is 1 or 2.

Embodiment 72

The compound of embodiments 66-71 having the formula:

Embodiment 73

The compound of embodiments 6-72 having the formula:

wherein, X¹ is CR²¹R^(21A), O, NR^(21A), or S; X² is CR²²R^(22A), O,NR^(22A), or S; R⁷ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(33I), —NR^(34I)R^(35I), —COOR^(33I), —CONR^(34I)R^(35I),—NO₂, —SR^(36I), —SO_(n9)R^(34I), —SO_(n9)OR^(34I),—SO_(n9)NR^(34I)R^(35I), —NHNR^(34I)R^(35I), —ONR^(34I)R^(35I),—NHC(O)NHNR^(34I)R^(35I), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹⁰and R¹¹ are independently hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —CHO, —OR^(33L), —NR^(34L)R^(35L), —COOR^(33L),—CONR^(34L)R^(35L), —NO₂, —SR^(36L), —SO_(n12)R^(34L),—SO_(n12)OR^(34L), —SO_(n12)NR^(34L)R^(35L), —NHNR^(34L)R^(35L),—ONR^(34L)R^(35L), —NHC(O)NHNR^(34L)R^(35L), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl, or are optionally joined together to form asubstituted or unsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, or a substitutedor unsubstituted heteroaryl; R¹², R¹³, R²¹, R^(21A), R²² and R^(22A) areindependently hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OR^(33M), —NR^(34M)R^(35M), —COOR^(33M), —CONR^(34M)R^(35M),—NO₂, —SR^(36M), —SO_(n13)R^(34M), —SO_(n13)OR^(34M),—SO_(n13)NR^(34M)R^(35M), —NR^(34M)R^(35M), —ONR^(34M)R^(35M),—NHC(O)NHNR^(34M)R^(35M), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(33M), R^(34M), R^(35M), and R^(36M) are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and n9, n11, and n13 areindependently 1 or 2.

Embodiment 74

The compound of embodiments 66-73 having the formula:

Embodiment 75

The compound of embodiments 66-74 having the formula:

wherein, X¹ is CR²¹R^(21A), O, NR^(21A), or S; X² is CR²²R^(22A), O,NR^(22A), or S; and R⁷ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —CHO, —OR^(33I), —NR^(34I)R^(35I), —COOR^(33I),—CONR^(34I)R^(35I), —NO₂, —SR^(36I), —SO_(n9)R^(34I), —SO_(n9)OR^(34I),—SO_(n9)NR^(34I)R^(35I), —NHNR^(34I)R^(35I), —ONR^(34I)R^(35I),—NHC(O)NHNR^(34I)R^(35I), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹¹is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(33L), —NR^(34L)R^(35L), —COOR^(33L), —CONR^(34L)R^(35L), —NO₂,—SR^(36L), —SO_(n12)R^(34L), —SO_(n12)OR^(34L),—SO_(n12)NR^(34L)R^(35L), —NHNR^(34L)R^(35L), —ONR^(34L)R^(35L),—NHC(O)NHNR^(34L)R^(35L), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl, orare optionally joined together to form a substituted or unsubstitutedcycloalkyl, a substituted or unsubstituted heterocycloalkyl, asubstituted or unsubstituted aryl, or a substituted or unsubstitutedheteroaryl; R¹², R¹³, R²¹, R^(21A), R²², and R^(22A) are independentlyhydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33M),—NR^(34M)R^(35M), —COOR^(33M), —CONR^(34M)R^(35M), —NO₂, —SR^(36M),—SO_(n13)R^(34M), —SO_(n13)OR^(34M), —SO_(n13)NR^(34M)R^(35M),—NHNR^(34M)R^(35M), —ONR^(34M)R^(35M), —NHC(O)NHNR^(34M)R^(35M),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹⁷ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33P), —NR^(34P)R^(35P),—COOR^(33P), —CONR^(34P)R^(35P), —NO₂, —SR^(36P), —SO_(n15)R^(34P),—SO_(n5)OR^(34P), —SO_(n15)NR^(34P)R^(35P), —NHNR^(34P)R^(35P),—ONR^(34P)R^(35P), —NHC(O)NHNR^(34P)R^(35P), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl, or are optionally bonded together to form asubstituted or unsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, or a substitutedor unsubstituted heteroaryl; R^(33I), R^(34I), R^(35I), R^(36I),R^(33L), R^(34L), R^(35L), R^(36L), R^(33M), R^(34M), R^(35M), R^(36M),R^(33P), R^(34P), R^(35P), and R^(36P) are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and n9, n12, n13 and n15 areindependently 1 or 2.

Embodiment 76

The compound of embodiments 66-75 having the formula:

Embodiment 77

A compound having the formula:

wherein, R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OR^(33A), —NR^(34A)R^(35A), —COOR^(33A), —CONR^(34A)R^(35A),—NO₂, —SR^(36A), —SO_(n1)R^(34A), —SO_(n1)OR^(34A),—SO_(n1)NR^(34A)R^(35A), —NHNR^(34A)R^(35A), —ONR^(34A)R^(35A),—NHC(O)NHNR^(34A)R^(35A), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R² ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33B),—NR^(34B)R^(35B), —COOR^(33B), —CONR^(34B)R^(35B), —NO₂, —SR^(36B),—SO_(n2)R^(34b), —SO_(n2)OR^(34B), —SO_(n2)NR^(34B)R^(35B),—NHNR^(34B)R^(35B), —ONR^(34B)R^(35B), —NHC(O)NHNR^(34B)R^(35B),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R³ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR³³C, —NR^(34C)R^(35C),—COOR^(33C), —CONR^(34C)R^(35C), —NO₂, —SR^(36C), —SO_(n3)R^(34C),—SO_(n3)OR^(34C), —SO_(n3)NR^(34C)R^(35C), —NHNR^(34C)R^(35C),—ONR^(34C)R^(35C), —NHC(O)NHNR^(34C)R^(35C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33D), —NR^(34D)R^(35D), —COOR^(33D),—CONR^(34D)R^(35D), —NO₂, —SR^(36D), —SO_(n4)R^(34D), —SO_(n4)OR^(34D),—SO_(n4)NR^(34D)R^(35D), —NHNR^(34D)R^(35D), —ONR^(34D)R^(35D),—NHC(O)NHNR^(34D)R^(35D), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33E),—NR^(34E)R^(35E), —COOR^(33E), —CONR^(34E)R^(35E), —NO₂, —SR^(36E),—SO_(n5)R^(34E), —SO_(n5)OR^(34E), —SO_(n5)NR^(34E)R^(35E),—NHNR^(34E)R^(35E), —ONR^(34E)R^(35E), —NHC(O)NHNR^(34E)R^(35E),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁶ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33F), —NR^(34F)R^(35F),—COOR^(33F), —CONR^(34F)R^(35F), —NO₂, —SR^(36F), —SO_(n6)R^(34F),—SO_(n6)OR^(34F), —SO_(n6)NR^(34F)R^(35F), —NHNR^(34F)R^(35F),—ONR^(34F)R^(35F), —NHC(O)NHNR^(34F)R^(35F), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R¹⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33G), —NR^(34G)R^(35G), —COOR^(33G),—CONR^(34G)R^(35G), —NO₂, —SR^(36G), —SO_(n7)R^(34G), —SO_(n7)OR^(34G),—SO_(n7)NR^(34G)R^(35G), —NHNR^(34G)R^(35G), —ONR^(34G)R^(35G),—NHC(O)NHNR^(34G)R^(35G), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹⁸is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(33H), —NR^(34H)R^(35H), —COOR^(33H), —CONR^(34H)R^(35H), —NO₂,—SR^(36H), —SO_(n8)R^(34H), —SO_(n8)OR^(34H), —SO_(n8)NR^(34H)R^(35H),—NHNR^(34H)R^(35H), —ONR^(34H)R^(35H), —NHC(O)NHNR^(34H)R^(35H),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(33A), R^(34A), R^(35A),R^(36A), R^(33B), R^(34B), R^(35B), R^(36B), R^(33C), R^(34C), R^(35C),R^(36C), R^(33D), R^(34D), R^(35D), R^(36D), R^(33E), R^(34E), R^(35E),R^(36E), R^(33F), R^(34F), R³⁵, R^(36F), R^(33G), R^(34G), R^(35G),R^(36G), R^(33H), R^(34H), R^(35H), and R^(36H) are independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; and n1,n2, n3, n4, n5, n6, n7, and n8 are independently 1 or 2.

Embodiment 78

The compound of embodiment 77 having formula

wherein, X³ is N or CR⁷; X⁴ is N or CR⁸; X⁵ is N or CR⁹; R⁷ is hydrogen,halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33I),—NR^(34I)R^(35I), —COOR^(33I), —CONR^(34I)R^(35I), —NO₂, —SR^(36I),—SO_(n9)R^(34I), —SO_(n9)OR^(34I), —SO_(n9)NR^(34I)R^(35I),—NHNR^(34I)R^(35I), —ONR^(34I)R^(35I), —NHC(O)NHNR^(34I)R^(35I),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁸ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR³³, —NR^(34J)R^(35J),—COOR^(33J), —CONR^(34J)R^(35J), —NO₂, —SR^(36J), —SO_(n10)R^(34J),—SO_(n10)OR^(34J), —SO_(n10)NR^(34J)R^(35J), —NHNR^(34J)R^(35J),—ONR^(34J)R^(35J), —NHC(O)NHNR^(34J)R^(35J), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33K), —NR^(34K)R^(35K), —COOR^(33K),—CONR^(34K)R^(35K), —NO₂, —SR^(36K), —SO_(n11)R^(34K),—SO_(n11)OR^(34K), —SO_(n11)NR^(34K)R^(35K), —NHNR^(34K)R^(35K),—ONR^(34K)R^(35K), —NHC(O)NHNR^(34K)R^(35K), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R¹⁰ and R¹¹ are independently hydrogen,halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33L),—NR^(34L)R^(35L), —COOR^(33L), —CONR^(34L)R^(35L), —NO₂, —SR^(36L),—SO_(n12)R^(34L), —SO_(n12)OR^(34L), —SO_(n12)NR^(34L)R^(35L),—NHNR^(34L)R^(35L), —ONR^(34L)R^(35L), —NHC(O)NHNR^(34L)R^(35L),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or are optionally joinedtogether to form a substituted or unsubstituted cycloalkyl, asubstituted or unsubstituted heterocycloalkyl, a substituted orunsubstituted aryl, or a substituted or unsubstituted heteroaryl;R^(33I), R^(34I), R^(35I), R^(36I), R^(33J), R^(34J), R^(35J), R^(36J),R^(33K), R^(34K), R^(35K), R^(36K), R^(33L), R^(34L), R^(35L), andR^(36L), are independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; andn9, n10, n11, and n12 are independently 1 or 2.

Embodiment 79

The compound of embodiments 77-78 having formula:

Embodiment 80

The compound of embodiment 77 having formula:

wherein, X⁶ is CR²¹ or N; X⁷ is CR²²R²³, S, O, or NR²³; R¹⁹, R²⁰, R²¹,R²² and R²³ are independently hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33M), —NR^(34M)R^(35M), —COOR^(33M),—CONR^(34M)R^(35M), —NO₂, —SR^(36M), —SO_(n13)R^(34M), —SO_(n3)OR^(34M),—SO_(n13)NR^(34M)R^(35M), —NHNR^(34M)R^(35M), —ONR^(34M)R^(35M),—NHC(O)NHNR^(34M)R^(35M), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(33M), R^(34M), R^(35M), and R^(36M) are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and n13 is 1 or 2.

Embodiment 81

The compound of embodiments 77 or 80 having formula:

Embodiment 82

The compound of embodiment 77 having formula:

wherein, X¹ is CR²¹R^(21A), O, NR^(21A), or S; X² is CR²²R^(22A), O,NR^(22A), or S; and R¹², R¹³, R¹⁴, R¹⁵ R²¹, R^(21A), R²², and R^(22A)are independently hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OR^(33M), —NR^(34M)R^(35M), —COOR^(33M), —CONR^(34M)R^(35M),—NO₂, —SR^(36M), —SO_(n3)R^(34M), —SO_(n13)OR³⁴M,—SO_(n13)NR^(34M)R^(35M), —NHNR^(34M)R^(35M), —ONR^(34M)R^(35M),—NHC(O)NHNR^(34M)R^(35M), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(33M), R^(34M), R^(35M), and R^(36M) are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and n13 is 1 or 2.

Embodiment 83

The compound of embodiments 77 or 82 having formula:

Embodiment 84

The compound of embodiment 77 having formula

wherein, X¹ is CR²¹R^(21A), O, NR^(21A), or S; X² is CR²²R^(22A), O,NR^(22A), or S; R⁷ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —CHO, —OR^(33I), —NR^(34I)R^(35I), —COOR^(33I), —CONR^(34I)R^(35I),—NO₂, —SR^(36I), —SO_(n9)R^(34I), —SO_(n9)OR^(34I),—SO_(n9)NR^(34I)R^(35I), —NHNR^(34I)R^(35I), —ONR^(34I)R^(35I),—NHC(O)NHNR^(34I)R^(35I), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹⁰and R¹¹ are independently hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —CHO, —OR^(33L), —N^(34L)R^(35L), —COOR^(33L),—CONR^(34L)R^(35L), —NO₂, —SR^(36L), —SO_(n12)R^(34L),—SO_(n12)OR^(34L), —SO_(n12)NR^(34L)R^(35L), —NHNR^(34L)R^(35L),—ONR^(34L)R^(35L), —NHC(O)NHNR^(34L)R^(35L), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl, or are optionally joined together to form asubstituted or unsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, or a substitutedor unsubstituted heteroaryl; R¹², R¹³, R²¹, R^(21A), R²² and R^(22A) areindependently hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OR^(33M), —NR^(34M)R^(35M), —COOR^(33M), —CONR^(34M)R^(35M),—NO₂, —SR^(36M), —SO_(n13)R^(34M), —SO_(n13)OR^(34M),—SO_(n13)NR^(34M)R^(35M), —NR^(34M)R^(35M), —ONR^(34M)R^(35M),—NHC(O)NHNR^(34M)R^(35M), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(33M), R^(34M), R^(35M), and R^(36M) are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and n9, n11, and n13 areindependently 1 or 2.

Embodiment 85

The compound of embodiments 77 or 84 having formula

Embodiment 86

The compound of embodiment 77 having formula

wherein, X¹ is CR²¹R^(21A), O, NR^(21A), or S; X² is CR²²R^(22A), O,NR^(22A), or S; and R⁷ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —CHO, —OR^(33I), —NR^(34I)R^(35I), —COOR^(33I),—CONR^(34I)R^(35I), —NO₂, —SR^(36I), —SO_(n9)R^(34I), —SO_(n9)OR^(34I),—SO_(n9)NR^(34I)R^(35I), —NHNR^(34I)R^(35I), —ONR^(34I)R^(35I),—NHC(O)NHNR^(34I)R^(35I), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹¹is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(33L), —NR^(34L)R^(35L), —COOR^(33L), —CONR^(34L)R^(35L), —NO₂,—SR^(36L), —SO_(n12)R^(34L), —SO_(n12)OR^(34L),—SO_(n12)NR^(34L)R^(35L), —NHNR^(34L)R^(35L), —ONR^(34L)R^(35L),—NHC(O)NHNR^(34L)R^(35L), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl, orare optionally joined together to form a substituted or unsubstitutedcycloalkyl, a substituted or unsubstituted heterocycloalkyl, asubstituted or unsubstituted aryl, or a substituted or unsubstitutedheteroaryl; R¹², R¹³, R²¹, R^(21A), R²², and R^(22A) are independentlyhydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33M),—NR^(34M)R^(35M), —COOR^(33M), —CONR^(34M)R^(35M), —NO₂, —SR^(36M),—SO_(n13)R^(34M), —SO_(n13)OR^(34M), —SO_(n13)NR^(34M)R^(35M),—NHNR^(34M)R^(35M), —ONR^(34M)R^(35M), —NHC(O)NHNR^(34M)R^(35M),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹⁷ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33P), —NR^(34P)R^(35P),—COOR^(33P), —CONR^(34P)R^(35P), —NO₂, —SR^(36P), —SO_(n15)R^(34P),—SO_(n15)OR^(34P), —SO_(n15)NR^(34P)R^(35P), —NHNR^(34P)R^(35P),—ONR^(34P)R^(35P), —NHC(O)NHNR^(34P)R^(35P), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl, or are optionally bonded together to form asubstituted or unsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, or a substitutedor unsubstituted heteroaryl; R^(33I), R^(34I), R^(35I), R^(36I),R^(33L), R^(34L), R^(35L), R^(36L), R^(33M), R^(34M), R^(35M), R^(36M),R^(33P), R^(34P), R^(35P), and R^(36P) are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and n9, n12, n13 and n15 areindependently 1 or 2.

Embodiment 87

The compound of embodiments 77 or 86 having formula

Embodiment 88

The compound of embodiment 1, wherein said compound is an epigeneticinhibitor.

Embodiment 89

The compound of embodiment 88, wherein said compound inhibits theactivity of HMT SUV39H1.

Embodiment 90

The compound of embodiments 88-89, wherein said compound specificallyinhibits the activity of HMT SUV39H1.

Embodiment 91

The compound of embodiments 88-90, wherein said compound inhibits theactivity of HMT G9a.

Embodiment 92

The compound of embodiments 88-91, wherein said compound specificallyinhibits the activity of HMT G9a

Embodiment 93

The compound of any one of embodiments 88-92, wherein said compoundinhibits the activity of HMT SUV39H1 and the activity of HMT G9a.

Embodiment 94

The compound of any one of embodiments 88-93, wherein said compoundspecifically inhibits the activity of HMT SUV39H1 and the activity ofHMT G9a.

Embodiment 95

The compound of embodiment 1, wherein said compound inhibits H3K9trimethylation or dimethylation.

Embodiment 96

A method of treating cancer, said method comprising administering to asubject in need thereof a therapeutically effective amount of a compoundof one of embodiment 1.

Embodiment 97

The method of embodiments 95-96, wherein said cancer is a solid or bloodtumor.

Embodiment 98

The method of embodiments 96 or 97, wherein said cancer is ovariancancer, breast cancer, lung cancer, leukemia, AML, CML, lymphoma,pancreatic cancer, kidney cancer, melanoma, liver cancer, colon cancer,sarcoma, multiple myeloma, brain cancer, or prostate cancer.

Embodiment 99

The method of embodiments 96-98, further comprising administering atleast one additional anticancer agent.

Embodiment 100

The method of embodiments 96 to 99, wherein said at least one additionalanticancer agent comprises an epigenetic inhibitor or a multi-kinaseinhibitor.

Embodiment 101

The method of embodiments 96 to 100, wherein said method comprisesadministering a first amount of said compound and a second amount of atleast one additional anticancer agent, wherein the first amount andsecond amount are together an effective amount to provide a synergistictherapeutic effect.

Embodiment 102

The method of embodiments 96 to 101, wherein said additional anticanceragent is an epigenetic inhibitor.

Embodiment 103

The method of embodiments 96 or 102, wherein said epigenetic inhibitoris azacitidine or decitadine.

Embodiment 104

The method of embodiments 96 to 103, wherein said compound and saidepigenetic inhibitor are co-administered as a pharmaceuticalcomposition.

Embodiment 105

The method embodiments 96-101, wherein said additional anticancer agentis a multi-kinase inhibitor.

Embodiment 106

The method of embodiments 96-105, wherein said multi-kinase inhibitor issorafenib.

Embodiment 107

The method of embodiment 96-105, wherein said compound and saidmulti-kinase inhibitor are co-administered as a pharmaceuticalcomposition.

Embodiment 108

The method of embodiments 96 to 107, wherein said cancer is ovariancancer.

Embodiment 109

A pharmaceutical composition comprising a compound of embodiment 1 and apharmaceutically acceptable excipient.

Embodiment 110

A pharmaceutical composition comprising a compound of embodiment 1 andat least one additional anticancer agent.

Embodiment 111

The pharmaceutical composition of embodiment 110, wherein said at leastone additional anticancer agent comprises a multi-kinase inhibitor or anepigenetic inhibitor.

Embodiment 112

The pharmaceutical composition of embodiments 110 or 111, wherein saidcombination includes a first amount of said compound and a second amountof a multi-kinase inhibitor, wherein the first amount and second amountare together an effective amount to provide a synergistic therapeuticeffect.

Embodiment 113

The pharmaceutical composition of embodiments 110 to 112, wherein saidcombination includes a first amount of said compound and a second amountof an epigenetic inhibitor, wherein the first amount and second amountare together an effective amount to provide a synergistic therapeuticeffect.

Embodiment 114

The pharmaceutical composition of embodiments 110 to 113, wherein saidcombination includes a first amount of said compound, a second amount ofa multi-kinase inhibitor, an a third amount of an epigenetic inhibitor,wherein the first amount, second, and third amounts are together aneffective amount to provide a synergistic therapeutic effect.

Embodiment 115

The pharmaceutical composition of any one of embodiments 109 to 113,wherein said multi-kinase inhibitor is sorafenib and said epigeneticinhibitor is azacitidine or decitadine.

Embodiment 116

The pharmaceutical composition of any one of embodiments 109 to 115, foruse in cancer.

Embodiment 117

The pharmaceutical composition of any one of embodiments 109 to 116, foruse in solid and blood tumors, including ovarian cancer, breast cancer,lung cancer, leukemia, AML, CML, lymphoma, pancreatic cancer, kidneycancer, melanoma, liver cancer, colon cancer, sarcoma, multiple myeloma,brain cancer, or prostate cancer.

Embodiment 118

The pharmaceutical composition of any one of embodiments 109 to 117, foruse in non-small cell lung cancer.

Embodiment 119

The pharmaceutical composition of any one of embodiments 109 to 118,wherein said compound and said multi-kinase inhibitor or said epigeneticinhibitor are co-administered as a single dosage form.

Embodiment 120

A compound having the formula:

wherein, p is 2, 3 or 4; and R¹, R², R³, R⁴, R⁵, R⁶, R¹⁶, and R¹⁸ areindependently hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

Embodiment 121

The compound of embodiment 120, wherein R¹⁸ is substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl.

Embodiment 122

The compound of embodiment 120-121 having the formula:

wherein, X³ is N or CR⁷; X⁴ is N or CR⁸; X⁵ is N or CR⁹; R⁷, R¹⁰ and R¹¹are independently hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁸ and R⁹ are independently hydrogen, halogen, —N₃, —NO₂,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —OCH₃, —NHCNHNH₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, wherein R⁸ and R⁹ areoptionally joined together to form a substituted or unsubstitutedcycloalkyl, a substituted or unsubstituted heterocycloalkyl, asubstituted or unsubstituted aryl, or a substituted or unsubstitutedheteroaryl; and p is 2, 3, or 4.

Embodiment 123

The compound of embodiment 120-122 having the formula:

Embodiment 124

The compound of embodiment 120-122 having the formula:

Embodiment 125

The compound of embodiment 120-122 having the formula:

Embodiment 126

The compound of any one of embodiments 122-125 having formula:

wherein, X¹ and X² are independently CH₂, O, NH, N, S, or Se; and R¹²,R¹³, R¹⁴, and R¹⁵ are independently hydrogen, halogen, —N₃, —NO₂, —CF₃,CCl₃, CBr₃, CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂; substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl, or are optionally bonded together to form asubstituted or unsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, or a substitutedor unsubstituted heteroaryl.

Embodiment 127

The compound of embodiment 126 having formula:

Embodiment 128

The compound of embodiment 127 having the formula:

Embodiment 129

The compound of any one of embodiments 120 to 129, wherein p is 2.

Embodiment 130

The compound of any one of embodiments 126-129 having formula:

Embodiment 131

The compound of embodiment 120 having formula:

wherein, X⁶ is CH, CR²¹, S, O, or N; X⁷ is CH₂, CR²², S, O, N, or NH;R¹⁹, R²⁰, R²¹, and R²² are independently hydrogen, halogen, —N₃, —NO₂,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂; substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl, or are optionally bonded together to form asubstituted or unsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, or a substitutedor unsubstituted heteroaryl.

Embodiment 132

The compound of any one of embodiments 120 or 131 having formula:

Embodiment 133

The compound of any one of embodiments 120 or 131 having formula:

Embodiment 134

The compound of any one of embodiments 120 or 131-133 having formula

Embodiment 135

The compound of any one of embodiments 120-125 having formula:

wherein, R¹² and R¹³ are independently hydrogen, halogen, —N₃, —CF₃,CCl₃, CBr₃, CI₃, —CN, —OH, —NH₂, —COOH, CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl, or are optionally bonded together to form asubstituted or unsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, or a substitutedor unsubstituted heteroaryl.

Embodiment 136

The compound of embodiment 135 having formula:

Embodiment 137

The compound of embodiment 135 having formula:

Embodiment 138

The compound of any one of embodiments 120-125 or 135-137 havingformula:

Embodiment 139

The compound of embodiment 138 having formula:

Embodiment 140

The compound of embodiment 138 having formula:

Embodiment 141

The compound of any one of embodiments 135 to 140, wherein p is 2.

Embodiment 142

The compound of any one of embodiment 120-128 or 135-141, wherein R¹ ishalogen, —N₃, —NO₂, —CF₃, CCl₃, CBr₃, CI₃, —CN, —CHO, —CONH₂, orsubstituted or unsubstituted heteroalkyl.

Embodiment 143

The compound of any one of embodiments 120-128 or 135-142, wherein R² ishalogen, —N₃, —NO₂, —CF₃, CCl₃, CBr₃, CI₃, —CN, —CHO, —CONH₂, orsubstituted or unsubstituted heteroalkyl.

Embodiment 144

The compound of any one of embodiments 120-128 or 135-142, wherein R¹ isCN.

Embodiment 145

The compound of any one of embodiments 120-128 or 135-144, wherein R¹ isC₁-C₅ substituted or unsubstituted heteroalkyl.

Embodiment 146

The compound of any one of embodiments 120-128 or 135-145, wherein R² isCN.

Embodiment 147

The compound of any one of embodiments 120-128 or 135-146, wherein R² isC₁-C₅ substituted or unsubstituted heteroalkyl.

Embodiment 148

The compound of embodiment 142, wherein said substituted or substitutedheteroalkyl provides polarity.

Embodiment 149

The compound of any one of embodiments 120-128 or 135-148, wherein R⁶ ishydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

Embodiment 150

The compound of any one of embodiments, 120-122, 126, 135, or 138,wherein R¹⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, C₁-C₃ substituted or unsubstitutedalkyl, or C₁-C₃ substituted or unsubstituted heteroalkyl.

Embodiment 151

The compound of any one of embodiments 120-128 or 135-140, wherein p is3.

Embodiment 152

The compound of any one of embodiments 135, 136, 138, or 140 havingformula:

Embodiment 153

The compound of any one of embodiments 120-125 having formula:

wherein, R⁸ is hydrogen or OCH₃; and R⁹ and R¹¹ are independentlyhydrogen or halogen.

Embodiment 154

The compound of any one of embodiments 120-125 having formula:

wherein, R⁸ is hydrogen or —OCH₃; and R⁹, R¹⁰, and R¹¹ are independentlyhydrogen or halogen.

Embodiment 155

The compound of any one of embodiments 135-140 having formula:

wherein; R⁵ is unsubstituted alkyl, unsubstituted heteroalkyl, orunsubstituted heterocycloalkyl; and p is 2 or 3.

Embodiment 156

The compound of embodiment 120 having the formula:

wherein, p is 2 or 4.

Embodiment 157

The compound of embodiment 155 or 156 wherein p is 2.

Embodiment 158

The compound of embodiment 120 having the formula:

Embodiment 159

The compound of any one of embodiments 120-128 or 135-140, wherein R¹ isCN and R² is substituted or unsubstituted C₂-C₂₀ alkyl, substituted orunsubstituted C₂-C₂₀ heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Embodiment 160

A compound having formula:

wherein, R¹⁷ is hydrogen, halogen, —N₃, —NO₂, —CF₃, CCl₃, CBr₃, CI₃,—CN, —OH, —NH₂, —COOH, CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂; substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl, orare optionally bonded together to form a substituted or unsubstitutedcycloalkyl, a substituted or unsubstituted heterocycloalkyl, asubstituted or unsubstituted aryl, or a substituted or unsubstitutedheteroaryl.

Embodiment 161

The compound of embodiment 160 having formula:

Embodiment 162

The compound of embodiment 160 having formula:

Embodiment 163

The compound of embodiment 160 having formula:

Embodiment 164

The compound of any one of embodiments 160 or 163 having formula:

Embodiment 165

The compound of any one of embodiments 152 or 160 having formula:

Embodiment 166

The compound of any one of embodiments 160-165 wherein p is 2.

Embodiment 167

The compound of any one of embodiments 160-165 having formula:

Embodiment 168

A compound having the formula:

wherein, R¹, R², R³, R⁴, R⁵, R⁶, R¹⁶, and R¹⁸ are independentlyhydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

Embodiment 169

A compound of Formula I:

wherein: X is selected from S₂, S₃, or S₄; R₁ is selected from H, alkyl,—C(═O)O-alkyl, alkoxy, R₇NHR₇, R₇NHR₈, R₇cycloalkyl, R₇aryl,R₇morpholinyl, heteroarylalkyl, R₇piperazinyl, or R₇piperazinyl with analkyl group substituted off the 4-N position of the piperazine ring; R₂is selected from H, alkyl, R₇NHR₇, R₇NHR₈, R₇cycloalkyl, R₇aryl,R₇morpholinyl, heteroarylalkyl, R₇piperazinyl, or R₇piperazinyl with analkyl group substituted off the 4-N position of the piperazine ring; R₃is selected from H, alkyl, aryl, heteroaryl, nitrile, F, Cl, OAc,—O-alkyl, or —O-aryl; R₄ is selected from alkyl, haloalkyl, biphenyl,thiophenyl, piperidyl, morpholinyl, imidazolyl, piperonyl, benzyl,cycloalkyl, benzodioxinyl, dioxinyl, benzodioxanyl, dioxanyl,benzoxazinyl, piperadinyl-1-methyl, heterocycle, indolyl, pyridinyl,piperazinyl, furyl, thienyl, heteroarylalkyl, or phenyl, or optionallysubstituted variants thereof; R₅ is selected from H, aryl, alkyl,haloalkyl, heteroaryl, phenyl, biphenyl, thiophenyl, piperidyl,morpholinyl, imidazolyl, piperonyl, benzyl, cycloalkyl, benzodioxinyl,dioxinyl, heterocycle, indolyl, or pyridinyl, or optionally substitutedvariants thereof; R₆ is selected from CN, NO₂, —S(O)₂alkyl, —S(O)₂aryl,—S(O)₂R₇, —S(O)₂CH₂CN, —(C═O)NH₂, —(N═H)OMe, —(C═O)(CH₂)₁₋₄CN,—(C═O)(CH₂)₁₋₄SO₂R₇, —(C═O)(CH₂)₁₋₄CO₂R₇, —(C═O)(CH₂)₁₋₄CO₂H,—(C═O)(CH₂)₁₋₄CH₂NH₂, —(C═O)(CH₂)₁₋₄CH₂NHCOR₅, —(C═O)(CH₂)₁₋₄CH₂NR₁R₂,(CH₂)₁₋₄OH, —(C═O)OH, —(C═O)O-alkyl, CH₂NHR₉, or CHR₁₀NHR₁₁; R₇ isalkyl; R₈ is selected from alkyl, heteroaryl, halo, alkoxy, thioalkyl,haloalkyl, NO₂, CN, —C(═O)O-alkyl, sulfonyl, or sulfonamide; R₉ isselected from H, alkyl, aryl, heteroaryl, acyl, or —O-carboxy; R₁₀ isselected from alkyl, aryl or heteroaryl; and R₁₁ is selected from H,alkyl, aryl, heteroaryl, acyl, or —O-carboxy.

Embodiment 170

The compound of embodiment 169, wherein X is S₂.

Embodiment 171

The compound of embodiments 169-170, wherein R₁ is methyl.

Embodiment 172

The compound of any one of the embodiments 169-171, wherein R₂ ismethyl.

Embodiment 173

The compound of any one of embodiments 169-172, wherein R₃ is methyl.

Embodiment 174

The compound of any one of embodiments 169-173, wherein R₄ is selectedfrom benzodioxinyl, phenyl optionally substituted with one or moresubstituents selected from the group consisting of halo and alkoxy, orpiperonyl.

Embodiment 175

The compound of embodiment 174, wherein R₄ is piperonyl.

Embodiment 176

The compound of any one of embodiments 169-175, wherein R₅ is H.

Embodiment 177

The compound of any one of embodiments 169-175, wherein R₅ is an aryloptionally substituted with one or more groups selected from —OH, —CN,NO₂, —C(═O), halo, haloalkyl, haloaryl, and heteroarylalkyl.

Embodiment 178

The compound of any one of embodiments 169-177, wherein R₆ is selectedfrom the group consisting of CN, —(C═O)O-tBu and —(C═O)OMe.

Embodiment 179

The compound of any one of embodiments 169-178, wherein R₇ is alkyl.

Embodiment 180

A compound of Formula II:

wherein: R₁ is selected from H, alkyl, —C(═O)O-alkyl, —C(═O)OR₇aryl,alkoxy, R₇NHR₈, R₇cycloalkyl, R₇aryl, R₇morpholinyl, heteroarylalkyl,R₇piperazinyl, or R₇piperazinyl with an alkyl group substituted off the4-N position of the piperazine ring; R₂ is selected from H, alkyl,R₇NHR₇, R₇NHR₈, R₇cycloalkyl, R₇aryl, R₇morpholinyl, heteroarylalkyl,R₇piperazinyl, or R₇piperazinyl with an alkyl group substituted off the4-N position of the piperazine ring; R₃ is selected from H, alkyl, aryl,heteroaryl, nitrile, F, Cl, OAc, O-alkyl, and O-aryl; R₄ is selectedfrom alkyl, haloalkyl, biphenyl, thiophenyl, piperidyl, morpholinyl,imidazolyl, piperonyl, benzyl, cycloalkyl, benzodioxinyl, dioxinyl,benzodioxanyl, dioxanyl, benzoxazinyl, piperadinyl-1-methyl,heterocycle, indolyl, pyridinyl, piperazinyl, furyl, thienyl,heteroarylalkyl, or phenyl, or optionally substituted variants thereof;R₅ is selected from H, aryl, alkyl, haloalkyl, heteroaryl, phenyl,biphenyl, thiophenyl, piperidyl, morpholinyl, imidazolyl, piperonyl,benzyl, cycloalkyl, benzodioxinyl, dioxinyl, heterocycle, indolyl, orpyridinyl, or optionally substituted variants thereof; R₆ is selectedfrom CN, NO₂, —S(O)₂alkyl, —S(O)₂aryl, —S(O)₂R₇, —S(O)₂CH₂CN, —(C═O)NH₂,—(N═H)OMe, —(C═O)(CH₂)₁₋₄CN; —(C═O)(CH₂)₁₋₄SO₂R₇; —(C═O)(CH₂)₁₋₄CO₂R₇;—(C═O)(CH₂)₁₋₄CO₂H; —(C═O)(CH₂)₁₋₄CH₂NH₂; —(C═O)(CH₂)₁₋₄CH₂NHCOR₅;—(C═O)(CH₂)₁₋₄CH₂NR₁R₂; (CH₂)₁₋₄OH, —(C═O)OH, —(C═O)O-alkyl; CH₂NHR₉, orCHR₁₀NHR₁₁; R₇ is alkyl; R₈ is selected from alkyl, heteroaryl, halo,alkoxy, thioalkyl, haloalkyl, NO₂, CN, —C(═O)O-alkyl, sulfonyl, orsulfonamide; R₉ is selected from H, alkyl, aryl, heteroaryl, acyl, or—O-carboxy; R₁₀ is selected from alkyl, aryl or heteroaryl; R₁₁ isselected from H, alkyl, aryl, heteroaryl, acyl, or —O-carboxy; and R₁₂is selected from methyl or a thiol-protecting group.

Embodiment 181

The compound of embodiment 180, wherein R₄ is selected frombenzodioxinyl, phenyl optionally substituted with one or moresubstituents selected from the group consisting of halo and alkoxy, orpiperonyl.

Embodiment 182

The compound of embodiment 180, wherein R₅ is an aryl optionallysubstituted with one or more groups selected from —OH, —CN, NO₂, —C(═O),halo, haloalkyl, haloaryl, and heteroarylalkyl.

Embodiment 183

A compound of Formula III:

wherein: X is selected from S₂, S₃, or S₄; R₁ is selected from H, alkyl,—C(═O)O, alkyl, alkoxy, R₇NHR₇, R₇NHR₈, R₇cycloalkyl, R₇aryl,R₇morpholinyl, heteroarylalkyl, R₇piperazinyl, or R₇piperazinyl with analkyl group substituted off the 4-N position of the piperazine ring; R₂is selected from H, alkyl, R₇NHR₇, R₇NHR₈, R₇cycloalkyl, R₇aryl,R₇morpholinyl, heteroarylalkyl, R₇piperazinyl, or R₇piperazinyl with analkyl group substituted off the 4-N position of the piperazine ring; R₇is alkyl; R₈ is selected from selected from alkyl, heteroaryl, halo,alkoxy, thioalkyl, haloalkyl, NO₂, CN, —C(═O)O-alkyl, sulfonyl, orsulfonamide; R₁₃ is selected from H, alkyl, aryl, heteroaryl, halo,alkoxy, thioalkyl, haloalkyl, NO₂, CN, —C(═O)O-alkyl, sulfonyl,sulfonamide or optionally substituted variants thereof; A is selectedfrom the group consisting of CH₂, C═O, NH, NR₁₄, O, S, and SO₂; B isselected from the group consisting of CH₂, C═O, NH, NR₁₄, O, S, and SO₂;C is selected from the group consisting of CH₂, C═O, NH, NR₁₄, O, S, andSO₂; and R₁₄ is selected from the group consisting of alkyl, aryl, acyl,and —O-carboxy.

Embodiment 184

The compound of embodiment 183, wherein R₁ is methyl.

Embodiment 185

The compound of any one of embodiments 183-184, wherein R₂ is methyl.

Embodiment 186

The compound of any one of embodiments 183-185, wherein A is selectedfrom C═O, NH, NR₁₄, O, S, and SO₂, and both B and C are CH₂.

Embodiment 187

The compound of any one of embodiments 183-185, wherein B is selectedfrom C═O, NH, NR₁₄, O, S, and SO₂, and both A and C are CH₂.

Embodiment 188

The compound of any one of embodiments 183-185, wherein C is selectedfrom C═O, NH, NR₁₄, O, S, and SO₂, and both A and B are CH₂.

Embodiment 189

The compound of any one of embodiments 183-185, wherein each of A, B andC is CH₂.

Embodiment 190

A compound from the genus of Formula IV:

wherein: X is selected from S₂, S₃, or S₄; R₁ is selected from H, alkyl,—C(═O)O, alkyl, alkoxy, R₇NHR₇, R₇NHR₈, R₇cycloalkyl, R₇aryl,R₇morpholinyl, heteroarylalkyl, R₇piperazinyl, or R₇piperazinyl with analkyl group substituted off the 4-N position of the piperazine ring; R₂is selected from H, alkyl, R₇NHR₇, R₇NHR₈, R₇cycloalkyl, R₇aryl,R₇morpholinyl, heteroarylalkyl, R₇piperazinyl, or R₇piperazinyl with analkyl group substituted off the 4-N position of the piperazine ring; R₇is alkyl; R₈ is selected from alkyl, heteroaryl, halo, alkoxy,thioalkyl, haloalkyl, NO₂, CN, —C(═O)O-alkyl, sulfonyl, or sulfonamide;R₁₂ is selected from methyl or a thiol-protecting group; R₁₃ is selectedfrom H, alkyl, aryl, heteroaryl, halo, alkoxy, thioalkyl, haloalkyl,NO₂, CN, —C(═O)O-alkyl, sulfonyl, or sulfonamide or optionallysubstituted variants thereof; A is selected from the group consisting ofCH₂, C═O, NH, NR₁₄, O, S, and SO₂; B is selected from the groupconsisting of CH₂, C═O, NH, NR₁₄, O, S, and SO₂; C is selected from thegroup consisting of CH₂, C═O, NH, NR₁₄, O, S, and SO₂; and R₁₄ isselected from the group consisting of alkyl, aryl, acyl, and —O-carboxy.

Embodiment 191

The compound of embodiment 190, wherein R₁ is selected from methyl orhydrogen.

Embodiment 192

The compound of embodiments 190-191, wherein R₂ is selected from methylor hydrogen.

Embodiment 193

The compound of any one of embodiments 190-192, wherein R₁₃ ispiperonyl.

Embodiment 194

The compound of any one of embodiments 190-192, wherein R₁₃ is a phenylsubstituted with one or more substituents selected from halo and alkoxy.

Embodiment 195

The compound of any one of embodiments 190-192, wherein R₁₃ is hydrogen.

Embodiment 196

The compound of any one of embodiments 190-192, wherein R₁₃ is CN.

Embodiment 197

The compound of any one of embodiments 190-192, wherein R₁₃ is—C(═O)O-alkyl.

Embodiment 198

The compound of any one of embodiments 190-197, wherein A is selectedfrom C═O, NH, NR₁₄, O, S, and SO₂, and both B and C are CH₂.

Embodiment 199

The compound of any one of embodiments 190-197, wherein B is selectedfrom C═O, NH, NR₁₄, O, S, and SO₂, and both A and C are CH₂.

Embodiment 200

The compound of any one of embodiments 190-197, wherein C is selectedfrom C═O, NH, NR₁₄, O, S, and SO₂, and both A and B are CH₂.

Embodiment 201

The compound of any one of embodiments 189-196, wherein each of A, B andC is CH₂.

Embodiment 202

A compound of Formula V for treating a diseased state:

Embodiment 203

A compound of Formula VI for treating a diseased state:

Embodiment 204

A compound of Formula VII for treating a diseased state:

Embodiment 205

A pharmaceutically acceptable salt, prodrug, hydrate, solvate, or acidsalt hydrate of the compound of any one of embodiments 170-204.

Embodiment 206

A pharmaceutical composition comprising an effective amount of acompound of any one of embodiments 170-204 or a pharmaceuticallyacceptable salt, prodrug, hydrate, solvate, or acid salt hydrate of thecompound of embodiment 205.

Embodiment 207

The pharmaceutical composition of embodiment 206, wherein thecomposition contains a stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide, prodrugester, or isomorphic crystalline form of the compound.

Embodiment 208

The pharmaceutical composition of any one of embodiments 206-207,wherein the compound is mixed with a pharmaceutically acceptablecarrier, diluent, excipient or combination thereof.

Embodiment 209

A method of dysregulating a histone methyltransferase comprisingadministering an effective amount of a compound of any one ofembodiments 170-204, a pharmaceutically-acceptable salt, prodrug,hydrate, solvate, or acid salt hydrate of embodiment 205, or apharmaceutical composition of any one of embodiments 206-208 to asubject in need thereof.

Embodiment 210

The method of embodiment 209, wherein the subject is a human.

Embodiment 211

The method of any one of embodiments 209-210, wherein the compound isselected from group consisting of:

Embodiment 212

A method for treating or preventing a disease condition comprisingadministering an effective amount of the compound of any one ofembodiments 170-204, a pharmaceutically-acceptable salt, prodrug,hydrate, solvate, or acid salt hydrate of embodiment 205, or apharmaceutical composition of any one of embodiments 206-208 to asubject in need of.

Embodiment 213

The method of embodiment 212, wherein the disease condition is selectedfrom cancer, diabetes, an infectious disease, an autoimmune disease, orpain.

Embodiment 214

The method of embodiment 213, wherein the cancer is selected fromprostate cancer, ovarian cancer, pancreatic cancer, chronic myelogenous(or myeloid) leukemia, or melanoma.

Embodiment 215

A compound of Formula VIII:

wherein: X is selected from S₂, S₃, or S₄; R₁ is selected from H, oralkyl, —C(═O)O-alkyl, alkoxy, R₇NHR₇, R₇NHR₈, R₇cycloalkyl, R₇aryl,R₇morpholinyl, heteroarylalkyl, R₇piperazinyl, or R₇piperazinyl with analkyl group substituted off the 4-N position of the piperazine ring; R₃is selected from H, alkyl, aryl or heteroaryl; R₄ is selected fromalkyl, haloalkyl, biphenyl, thiophenyl, piperidyl, morpholinyl,imidazolyl, piperonyl, benzyl, cycloalkyl, benzodioxinyl, dioxinyl,benzodioxanyl, dioxanyl, benzoxazinyl, piperadinyl-1-methyl,heterocycle, indolyl, pyridinyl, piperazinyl, furyl, thienyl,heteroarylalkyl, or phenyl, or optionally substituted variants thereof;R₅ is selected from H, aryl, alkyl, haloalkyl, heteroaryl, phenyl,biphenyl, thiophenyl, piperidyl, morpholinyl, imidazolyl, piperonyl,benzyl, cycloalkyl, benzodioxinyl, dioxinyl, heterocycle, indolyl, orpyridinyl, or optionally substituted variants thereof; R₆ is selectedfrom CN, NO₂, —S(O)₂alkyl, —S(O)₂aryl, —S(O)₂R₇, —S(O)₂CH₂CN, —(C═O)NH₂,—(N═H)OMe, —(C═O)(CH₂)₁₋₄CN; —(C═O)(CH₂)₁₋₄SO₂R₇; —(C═O)(CH₂)₁₋₄CO₂R₇;—(C═O)(CH₂)₁₋₄CO₂H; —(C═O)(CH₂)₁₋₄CH₂NH₂; —(C═O)(CH₂)₁₋₄CH₂NHCOR₈;—(C═O)(CH₂)₁₋₄CH₂NR₁R₂; (CH₂)₁₋₄OH, —(C═O)OH, —(C═O)O-alkyl; CH₂NHR₉ orCHR₁₀NHR₁₁; R₇ is selected from H or alkyl; R₈ is selected from alkyl,heteroaryl, halo, alkoxy, thioalkyl, haloalkyl, NO₂, CN, —C(═O)O-alkyl,sulfonyl, or sulfonamide; R₉ is selected from H, alkyl, aryl,heteroaryl, acyl, or —O-carboxy; R₁₀ is selected from alkyl, aryl orheteroaryl; and R₁₁ is selected from H, alkyl, aryl, heteroaryl, acyl,or —O-carboxy; and R₁₅ is selected from —OH, —Oaryl, —Oalkyl, Cl, F,—O-carboxy, or N₃.

Embodiment 216

The compound of embodiment 215, wherein R₁ is methyl.

Embodiment 217

The compound of embodiments 215-216, wherein R₃ is methyl.

Embodiment 218

The compound of any one of embodiments 215-216, wherein R₄ is selectedfrom benzodioxinyl, phenyl optionally substituted with one or moresubstituents selected from the group consisting of halo and alkoxy, orpiperonyl.

Embodiment 219

The compound of embodiment 218, wherein R₄ is piperonyl.

Embodiment 220

The compound of any one of embodiments 215-219, wherein R₅ is H.

Embodiment 221

The compound of any one of embodiments 215-219, wherein R₅ is an aryloptionally substituted with one or more groups selected from —OH, —CN,NO₂, —C(═O), halo, haloalkyl, haloaryl, and heteroarylalkyl.

Embodiment 222

The compound of any one of embodiments 215-219, wherein R₆ is selectedfrom the group consisting of CN, —(C═O)O-tBu and —(C═O)OMe.

Embodiment 223

A compound of Formula IX:

wherein: X is selected from S₂, S₃, or S₄; R₁ is selected from H, alkyl,—C(═O)O, alkyl, alkoxy, R₇NHR₇, R₇NHR₈, R₇cycloalkyl, R₇aryl,R₇morpholinyl, heteroarylalkyl, R₇piperazinyl, or R₇piperazinyl with analkyl group substituted off the 4-N position of the piperazine ring; R₂is selected from H, alkyl, R₇NHR₇, R₇NHR₈, R₇cycloalkyl, R₇aryl,R₇morpholinyl, heteroarylalkyl, R₇piperazinyl, or R₇piperazinyl with analkyl group substituted off the 4-N position of the piperazine ring; R₇is selected from H or alkyl; R₈ is selected from alkyl, heteroaryl,halo, alkoxy, thioalkyl, haloalkyl, NO₂, CN, —C(═O)O-alkyl, sulfonyl, orsulfonamide; R₁₃ is selected from H, alkyl, aryl, heteroaryl, halo,alkoxy, thioalkyl, haloalkyl, NO₂, CN, —C(═O)O-alkyl, sulfonyl, orsulfonamide; or optionally substituted variants thereof; A is selectedfrom the group consisting of CH₂, C═O, NH, NR₁₄, O, S, and SO₂; B isselected from the group consisting of CH₂, C═O, NH, NR₁₄, O, S, and SO₂;C is selected from the group consisting of CH₂, C═O, NH, NR₁₄, O, S, andSO₂; and R₁₅ is selected from the group consisting of alkyl, aryl, acyl,and —O-carboxy.

Embodiment 224

A method for synthesizing a compound of embodiment 170, comprisingreacting a compound of Formula VIII with R₂NH₂ to form adiketopiperazine ring; introducing the sulfur ring to form a compound ofFormula I:

wherein X is selected from S₂, S₃, or S₄; R₁ is selected from H, alkyl,—C(═O)O-alkyl, alkoxy, R₇NHR₇, R₇NHR₈, R₇cycloalkyl, R₇aryl,R₇morpholinyl, heteroarylalkyl, R₇piperazinyl, or R₇piperazinyl with analkyl group substituted off the 4-N position of the piperazine ring; R₂is selected from H, alkyl, R₇NHR₇, R₇NHR₈, R₇cycloalkyl, R₇aryl,R₇morpholinyl, heteroarylalkyl, R₇piperazinyl, or R₇piperazinyl with analkyl group substituted off the 4-N position of the piperazine ring; R₃is selected from H, alkyl, aryl or heteroaryl; R₄ is selected fromalkyl, haloalkyl, biphenyl, thiophenyl, piperidyl, morpholinyl,imidazolyl, piperonyl, benzyl, cycloalkyl, benzodioxinyl, dioxinyl,benzodioxanyl, dioxanyl, benzoxazinyl, piperadinyl-1-methyl,heterocycle, indolyl, pyridinyl, piperazinyl, furyl, thienyl,heteroarylalkyl, or phenyl, or optionally substituted variants thereof;R₅ is selected from H, aryl, alkyl, haloalkyl, heteroaryl, phenyl,biphenyl, thiophenyl, piperidyl, morpholinyl, imidazolyl, piperonyl,benzyl, cycloalkyl, benzodioxinyl, dioxinyl, heterocycle, indolyl, orpyridinyl, or optionally substituted variants thereof; R₆ is selectedfrom CN, NO₂, —S(O)₂alkyl, —S(O)₂aryl, —S(O)₂R₇, —S(O)₂CH₂CN, —(C═O)NH₂,—(N═H)OMe, —(C═O)(CH₂)₁₋₄CN; —(C═O)(CH₂)₁₋₄SO₂R₇; —(C═O)(CH₂)₁₋₄CO₂R₇;—(C═O)(CH₂)₁₋₄CO₂H; —(C═O)(CH₂)₁₋₄CH₂NH₂; —(C═O)(CH₂)₁₋₄CH₂NHCOR₈;—(C═O)(CH₂)₁₋₄CH₂NR₁R₂; (CH₂)₁₋₄OH, —(C═O)OH, —(C═O)O-alkyl; CH₂NHR₉ orCHR₁₀NHR₁₁; R₇ is selected from H or alkyl; R₈ is selected from alkyl,heteroaryl, halo, alkoxy, thioalkyl, haloalkyl, NO₂, CN, —C(═O)O-alkyl,sulfonyl, or sulfonamide; R₉ is selected from H, alkyl, aryl,heteroaryl, acyl, or —O-carboxy; R₁₀ is selected from alkyl, aryl orheteroaryl; R₁₁ is selected from H, alkyl, aryl, heteroaryl, acyl, or—O-carboxy; and R₁₅ is selected from —OH, —Oaryl, —Oalkyl, Cl, F,—O-carboxy, or N₃.

Embodiment 225

A method of synthesizing a compound of embodiment 180 comprising:reacting a compound of Formula VIII with R₂NH₂ to form adiketopiperazine ring; introducing two thioether substituents to form acompound of Formula II:

wherein: R₁ is selected from H, alkyl, —C(═O)O-alkyl, —C(═O)OR₇aryl,alkoxy, R₇NHR₈, R₇cycloalkyl, R₇aryl, R₇morpholinyl, heteroarylalkyl, orR₇piperazinyl, R₇piperazinyl with an alkyl group substituted off the 4-Nposition of the piperazine ring; R₂ is selected from H, alkyl, R₇NHR₇,R₇NHR₈, R₇cycloalkyl, R₇aryl, R₇morpholinyl, heteroarylalkyl,R₇piperazinyl, or R₇piperazinyl with an alkyl group substituted off the4-N position of the piperazine ring; R₃ is selected from H, alkyl, aryl,heteroaryl, nitrile, F, Cl, OAc, O-alkyl, or O-aryl; R₄ is selected fromalkyl, haloalkyl, biphenyl, thiophenyl, piperidyl, morpholinyl,imidazolyl, piperonyl, benzyl, cycloalkyl, benzodioxinyl, dioxinyl,benzodioxanyl, dioxanyl, benzoxazinyl, piperadinyl-1-methyl,heterocycle, indolyl, pyridinyl, piperazinyl, furyl, thienyl,heteroarylalkyl, or phenyl, or optionally substituted variants thereof;R₅ is selected from H, aryl, alkyl, haloalkyl, heteroaryl, phenyl,biphenyl, thiophenyl, piperidyl, morpholinyl, imidazolyl, piperonyl,benzyl, cycloalkyl, benzodioxinyl, dioxinyl, heterocycle, indolyl, orpyridinyl, or optionally substituted variants thereof; R₆ is selectedfrom CN, NO₂, —S(O)₂alkyl, —S(O)₂aryl, —S(O)₂R₇, —S(O)₂CH₂CN, —(C═O)NH₂,—(N═H)OMe, —(C═O)(CH₂)₁₋₄CN; —(C═O)(CH₂)₁₋₄SO₂R₇; —(C═O)(CH₂)₁₋₄CO₂R₇;—(C═O)(CH₂)₁₋₄CO₂H; —(C═O)(CH₂)₁₋₄CH₂NH₂; —(C═O)(CH₂)₁₋₄CH₂NHCOR₅;—(C═O)(CH₂)₁₋₄CH₂NR₁R₂; (CH₂)₁₋₄OH, —(C═O)OH, —(C═O)O-alkyl; CH₂NHR₉,CHR₁₀NHR₁₁; R₇ is alkyl; R₈ is selected from alkyl, heteroaryl, halo,alkoxy, thioalkyl, haloalkyl, NO₂, CN, —C(═O)O-alkyl, sulfonyl, orsulfonamide; R₉ is selected from H, alkyl, aryl, heteroaryl, acyl, or—O-carboxy; R₁₀ is selected from alkyl, aryl or heteroaryl; R₁₁ isselected from H, alkyl, aryl, heteroaryl, acyl, or —O-carboxy; R₁₂ isselected from methyl or a thiol-protecting group; and R₁₅ is selectedfrom —OH, —Oaryl, —Oalkyl, Cl, F, —O-carboxy, or N₃.

Embodiment 226

A method for synthesizing a compound of embodiment 183 comprising:reacting a compound of Formula VIII with R₂NH₂ to form adiketopiperazine ring; introducing the sulfur ring to form a compound ofFormula III:

wherein: X is selected from S₂, S₃, or S₄; R₁ is selected from H, alkyl,—C(═O)O, alkyl, alkoxy, R₇NHR₇, R₇NHR₈, R₇cycloalkyl, R₇aryl,R₇morpholinyl, heteroarylalkyl, R₇piperazinyl, or R₇piperazinyl with analkyl group substituted off the 4-N position of the piperazine ring; R₂is selected from H, alkyl, R₇NHR₇, R₇NHR₈, R₇cycloalkyl, R₇aryl,R₇morpholinyl, heteroarylalkyl, R₇piperazinyl, or R₇piperazinyl with analkyl group substituted off the 4-N position of the piperazine ring; R₇is alkyl; R₈ is selected from alkyl, heteroaryl, halo, alkoxy,thioalkyl, haloalkyl, NO₂, CN, —C(═O)O-alkyl, sulfonyl, or sulfonamide;R₁₃ is selected from H, alkyl, aryl, heteroaryl, halo,

1.-119. (canceled)
 120. A compound having formula:

wherein: p is 2; X¹ is CR²¹R^(21A), O, NR^(21A), or S; X² isCR²²R^(22A), O, NR^(22A), or S; R¹ is hydrogen, halogen, —N₃, —CF₃,—CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33A), —NR^(34A)R^(35A), —COOR^(33A),—CONR^(34A)R^(35A), —NO₂, —SR^(36A), —SO_(n1)R^(34A), —SO_(n1)OR^(34A),—SO_(n1)NR^(34A)R^(35A), —NHNR^(34A)R^(35A), —ONR^(34A)R^(35A),—NHC(O)NHNR^(34A)R^(35A), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R² ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33B),—NR^(34B)R^(35B), —COOR^(33B), —CONR^(34B)R^(35B), —NO₂, —SR^(36B),—SO_(n2)R^(34B), —SO_(n2)OR^(34B), —SO_(n2)NR^(34B)R^(35B),—NHNR^(34B)R^(35B), —ONR^(34B)R^(35B), —NHC(O)NHNR^(34B)R^(35B),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R³ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33C), —NR^(34C)R^(35C),—COOR^(33C), —CONR^(34C)R^(35C), —NO₂, —SR^(36C), —SO_(n3)R^(34C),—SO_(n3)OR^(34C), —SO_(n3)NR^(34C)R^(35C), —NHNR³⁴R³⁵,—ONR^(34C)R^(35C), —NHC(O)NHNR^(34C)R^(35C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33D), —NR^(34D)R^(35D), —COOR^(33D),—CONR^(34D)R^(35D), —NO₂, —SR^(36D), —SO_(n4)R^(34D), —SO_(n4)OR^(34D),—SO_(n4)NR^(34D)R^(35D), —NHNR^(34D)R^(35D), —ONR^(34D)R^(35D),—NHC(O)NHNR^(34D)R^(35D), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33E),—NR^(34E)R^(35E), —COOR^(33E), —CONR^(34E)R^(35E), —NO₂, —SR^(36E),—SO_(n5)R^(34E), —SO_(n5)OR^(34E), —SO_(n5)NR^(34E)R^(35E),—NHNR^(34E)R^(35E), —ONR^(34E)R^(35E), —NHC(O)NHNR^(34E)R^(35E),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁶ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33F), —NR^(34F)R^(35F),—COOR^(33F), —CONR^(34F)R^(35F), —NO₂, —SR^(36F), —SO_(n6)R^(34F),—SO_(n6)OR^(34F), —SO_(n6)NR_(34F)R^(35F), —NHNR^(34F)R^(35F),—ONR^(34F)R^(35F), —NHC(O)NHNR^(34F)R^(35F), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁷ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33I), —NR^(34I)R^(35I), —COOR^(33I),—CONR^(34I)R^(35I), —NO₂, —SR^(36I), —SO_(n9)R^(34I), —SO_(n9)OR^(34I),—SO_(n9)NR^(34I)R^(35I), —NHNR^(34I)R^(35I), —ONR^(34I)R^(35I),—NHC(O)NHNR^(34I)R^(35I), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹⁰and R¹¹ are independently hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —CHO, —OR^(33L), —NR^(34L)R^(35L), —COOR^(33L),—CONR^(34L)R^(35L), —NO₂, —SR^(36L), —SO_(n12)R^(34L),—SO_(n12)OR^(34L), —SO_(n12)NR^(34L)R^(35L), —NHNR^(34L)R^(35L),—ONR^(34L)R^(35L), —NHC(O)NHNR^(34L)R^(35L), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl, or are optionally joined together to form asubstituted or unsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, or a substitutedor unsubstituted heteroaryl; R¹² and R¹³ are independently hydrogen,halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33M),—NR^(34M)R^(35M), —COOR^(33M), —CONR^(34M)R^(35M), —NO₂, —SR^(36M),—SO_(n13)R^(34M), —SO_(n13)OR^(34M), —SO_(n3)R^(34M)R^(35M),—NHNR^(34M)R^(35M), —ONR^(34M)R^(35M), —NHC(O)NHNR^(34M)R^(35M),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R²¹, R^(21A), R²² and R^(22A)are independently hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—CHO, —OR^(33M), —NR^(34M)R^(35M), —COOR^(33M), —CONR^(34M)R^(35M),—NO₂, —SR^(36M), —SO_(n13)R^(34M), —SO_(n13)OR^(34M),—SO_(n13)NR^(34M)R^(35M), —NHNR^(34M)R^(35M), —ONR^(34M)R^(35M),—NHC(O)NHNR^(34M)R^(35M), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; andR^(33A), R^(34A), R^(35A), R^(36A), R^(33B), R^(34B), R^(35B), R^(36B),R^(33C), R^(34C), R^(35C), R^(36C), R^(33D), R^(34D), R^(35D), R^(36D),R^(33E), R^(34E), R^(35E), R^(36E), R^(33F), R^(34F), R^(35F), R^(36F),R^(33I), R^(34I), R^(35I), R^(36I), R^(33L), R^(34L), R^(35L), R^(36L),R^(33M), R^(34M), R^(35M), and R^(36M) are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and n1, n2, n3, n4, n5, n6, n9,n12, and n13 are independently 1 or
 2. 121. The compound of claim 120,having formula:


122. The compound of claim 121, wherein X¹ and X² are independently O orS.
 123. The compound of claim 121, having formula:


124. The compound of claim 120, wherein R¹ is hydrogen, halogen, —CF₃,—CN, —CHO, —OR^(33A), —NR^(34A)R^(35A), —COOR^(33A), —CONR^(34A)R^(35A),—SR^(36A), —NHNR^(34A)R^(35A), —ONR^(34A)R^(35A),—NHC(O)NHNR^(34A)R^(35A), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, or substituted or unsubstituted heterocycloalkyl.
 125. Thecompound of claim 124, wherein R¹ is hydrogen, halogen, —CF₃, —CN,—OR^(33A), —NR^(34A)R^(35A), —COOR^(33A), —CONR^(34A)R^(35A), orsubstituted or unsubstituted alkyl.
 126. The compound of claim 125,wherein: R¹ is hydrogen, —CN, —OR^(33A), —NR^(34A)R^(35A), —COOR^(33A),—CONR^(34A)R^(35A), or substituted or unsubstituted alkyl, and R^(33A),R^(34A), and R^(35A) are independently hydrogen, or substituted orunsubstituted alkyl.
 127. The compound of claim 124, wherein R² ishydrogen, halogen, —CF₃, —CN, —OR^(33B), —NR^(34B)R^(35B), —COOR^(33B),—CONR^(34B)R^(35B), or substituted or unsubstituted alkyl.
 128. Thecompound of claim 127, wherein: R² is hydrogen, —CN, —OR^(33B),—NR^(34B)R^(35B), —COOR^(33B), —CONR^(34B)R^(35B), or substituted orunsubstituted alkyl; and R^(33B), R^(34B), and R^(35B) are independentlyhydrogen or substituted or unsubstituted alkyl.
 129. The compound ofclaim 127, wherein: R³ is hydrogen, halogen, —CF₃, —CN, —CHO, —OR^(33C),—NR^(34C)R^(35C), —COOR^(33C), —CONR^(34C)R^(35C), —NO₂, —SR^(36C),—NHNR^(34C)R^(35C), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocycloalkyl; and R⁴ is hydrogen,halogen, —CF₃, —CN, —CHO, —OR^(33D), —NR^(34D)R^(35D), —COOR^(33D),—CONR^(34D)R^(35D), —NO₂, —SR^(36D), —NHNR^(34D)R^(35D), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocycloalkyl.
 130. The compound of claim 129, wherein: R³ ishydrogen, halogen, —CF₃, —CN, —OR^(33C), or substituted or unsubstitutedalkyl; and R⁴ is hydrogen, halogen, —CF₃, —CN, —OR^(33D), or substitutedor unsubstituted alkyl.
 131. The compound of claim 129, wherein R⁵ ishydrogen, halogen, —CF₃, —CN, —CHO, —OR^(33E), —NR^(34E)R^(35E),—COOR^(33E), —CONR^(34E)R^(35E), —NO₂, substituted or unsubstitutedalkyl, or substituted or unsubstituted heteroalkyl.
 132. The compound ofclaim 131, wherein R⁵ is hydrogen, —F, —Cl, —Br, —I, —CF₃, orsubstituted or unsubstituted alkyl.
 133. The compound of claim 131,wherein R⁶ is hydrogen, halogen, —CF₃, —CN, —CHO, —OR^(33F),—NR^(34F)R^(35F), —COOR^(33F), —CONR^(34F)R^(35F), —NO₂, substituted orunsubstituted alkyl, or substituted or unsubstituted heteroalkyl. 134.The compound of claim 133, wherein R⁶ is hydrogen, —F, —Cl, —Br, —I,—CF₃, or substituted or unsubstituted alkyl.
 135. The compound of claim133, wherein: R⁷ is hydrogen, halogen, —CF₃, —CN, —CHO, —OR³³, orsubstituted or unsubstituted alkyl; R¹⁰ is hydrogen, halogen, —CF₃, —CN,—CHO, —OR^(33L), or substituted or unsubstituted alkyl; and R¹¹ ishydrogen, halogen, —CF₃, —CN, —CHO, —OR^(33L), substituted orunsubstituted alkyl; or R¹⁰ and R¹¹ are joined together to form asubstituted or unsubstituted cycloalkyl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl, or a substitutedor unsubstituted heteroaryl.
 136. The compound of claim 134, wherein:R¹² is hydrogen, halogen, —CF₃, —CN, —OR^(33M), —NR^(34M)R^(35M),—COOR^(33M), —CONR^(34M)R^(35M), —NO₂, —SR^(36M), substituted orunsubstituted alkyl; and R¹³ is hydrogen, halogen, —CF₃, —CN, —OR^(33M),—NR^(34M)R^(35M), —COOR^(33M), —CONR^(34M)R^(35M), or substituted orunsubstituted alkyl.
 137. The compound of claim 136, wherein R¹² ishydrogen, —F, —Cl, —Br, —I, —CF₃, or —CN; and R¹³ is hydrogen, —F, —Cl,—Br, —I, —CF₃, or —CN.
 138. A method of treating cancer, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound having formula:

wherein: p is 2, 3 or 4; R¹ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33A), —NR^(34A)R^(35A), —COOR^(33A),—CONR^(34A)R^(35A), —NO₂, —SR^(36A), —SO_(n1)R^(34A), —SO_(n1)OR^(34A),—SO_(n1)NR^(34A)R^(35A), —NHNR^(34A)R^(35A), —ONR^(34A)R^(35A),—NHC(O)NHNR^(34A)R^(35A), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R² ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33B),—NR^(34B)R^(35B), —COOR^(33B), —CONR^(34B)R^(35B), —NO₂, —SR^(36B),—SO_(n2)R^(34B), —SO_(n2)OR^(34B), —SO_(n2)NR^(34B)R^(35B),—NHNR^(34B)R^(35B), —ONR^(34B)R^(35B), —NHC(O)NHNR^(34B)R^(35B),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R³ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33C), —NR^(34C)R^(35C),—COOR^(33C), —CONR^(34C)R^(35C), —NO₂, —SR^(36C), —SO_(n3)R^(34C),—SO_(n3)OR^(34C), —SO_(n3)NR^(34C)R^(35C), —NHNR^(34C)R^(35C),—ONR^(34C)R^(35C), —NHC(O)NHNR^(34C)R^(35C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁴ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33D), —NR^(34D)R^(35D), —COOR^(33D),—CONR^(34D)R^(35D), —NO₂, —SR^(36D), —SO_(n4)R^(34D), —SO_(n4)OR^(34D),—SO_(n4)NR^(34D)R^(35D), —NHNR^(34D)R^(35D), —ONR^(34D)R^(35D),—NHC(O)NHNR^(34D)R^(35D), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ ishydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33E),—NR^(34E)R^(35E), —COOR^(33E), —CONR^(34E)R^(35E), —NO₂, —SR^(36E),—SO_(n5)R^(34E), —SO_(n5)OR^(34E), —SO_(n5)NR^(34E)R^(35E),—NHNR^(34E)R^(35E), —ONR^(34E)R^(35E), —NHC(O)NHNR^(34E)R^(35E),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁶ is hydrogen, halogen, —N₃,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OR^(33F), —NR^(34F)R^(35F),—COOR^(33F), —CONR^(34F)R^(35F), —NO₂, —SR^(36F), —SO_(n6)R^(34F),—SO_(n6)OR^(34F), —SO_(n6)NR^(34F)R^(35F), —NHNR^(34F)R^(35F),—ONR^(34F)R^(35F), —NHC(O)NHNR^(34F)R^(35F), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R¹⁶ is hydrogen, halogen, —N₃, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —CHO, —OR^(33G), —NR^(34G)R^(35G), —COOR^(33G),—CONR^(34G)R^(35G), —NO₂, —SR^(36G), —SO_(n7)R^(34G), —SO_(n7)R^(34G),—SO_(n7)NR^(34G)R^(35G), —NHNR^(34G)R^(35G), —ONR^(34G)R^(35G),—NHC(O)NHNR^(34G)R^(35G), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹⁸is hydrogen, halogen, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OR^(33H), —NR^(34H)R^(35H), —COOR^(33H), —CONR^(34H)R^(35H), —NO₂,—SR^(36H), —SO_(n8)R^(34H), —SO_(n8)OR^(34H), —SO_(n8)NR^(34H)R^(35H),—NHNR^(34H)R^(35H), —ONR^(34H)R^(35H), —NHC(O)NHNR^(34H)R^(35H),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(33A), R^(34A), R^(35A),R^(36A), R^(33B), R^(34B), R^(35B), R^(36B), R^(34C), R^(35C), R^(36C),R^(34D), R^(35D), R^(36D), R^(33E), R^(34E), R^(35E), R^(36E), R^(33F),R^(34F), R^(35F), R^(36F), R^(33G), R^(34G), R^(35G), R^(36G), R^(33H),R^(34H), R^(35H), and R^(36H) are independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(33c) and R^(33D) are independentlysubstituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and n1, n2, n3, n4, n5, n6, n7,and n8 are independently 1 or
 2. 139. The method of claim 138, whereinsaid cancer is ovarian cancer, breast cancer, lung cancer, leukemia,acute myeloid leukemia, chronic myeloid leukemia, lymphoma, pancreaticcancer, kidney cancer, melanoma, liver cancer, colon cancer, sarcoma,multiple myeloma, brain cancer, or prostate cancer.